Treating acne with oral contraceptives: use of lower doses

Contraception 73 (2006) 23 29 Review article Treating acne with oral contraceptives: use of lower doses Johannes HuberT, Katharina Walch Division of Gynecology and Infertility Treatment, Department of Obstetrics and Gynecology, Medical University Vienna, A-1090 Vienna, Austria Received 22 September 2004; revised 3 May 2005; accepted 21 July 2005 Abstract Oral contraceptives (OCs) have been shown to effectively treat acne. Clinical trials of various doses of ethinyl estradiol (EE) combined with progestins such as levonorgestrel, desogestrel, norgestimate, gestodene, cyproterone acetate and drospirenone in monophasic, triphasic and combiphasic formulations used to treat acne in women are reviewed here. Open-label and comparative studies beginning in the 1980s were the first to demonstrate objective and subjective reductions in the incidence of acne, severity of existing acne and seborrhea. Placebocontrolled trials have corroborated these findings with a trend toward effective acne treatment with declining doses of EE. Significant reductions in total, inflammatory and noninflammatory lesions compared with placebo have been demonstrated with an OC containing the low dose of 20 Ag of EE. Collectively, these findings support the use of low-dose OCs for the treatment of acne. D 2006 Elsevier Inc. All rights reserved. Keywords: Acne; Ethinyl estradiol; Levonorgestrel; Low-dose; Oral contraceptives 1. Introduction Acne is a multifactorial disease affecting the pilosebaceous units of the skin and is characterized by abnormal keratinization, increased sebum production, bacterial infection and local inflammation [1]. This common skin disorder has a profound economic as well as psychosocial impact on those who suffer from its symptoms. Physicians have known for many years that oral contraceptives (OCs) can reduce the incidence of acne and help diminish acne lesions [1]. The mechanism by which OCs improve acne most likely involves a decrease in the amount of circulating androgens. Specifically, OCs reduce total and bioavailable testosterone and increase the production of sex hormone binding globulin [2 4]. In addition, the steroids in OCs suppresses pituitary gonadotropin secretion, thereby decreasing the levels of ovarian androgens [1,5]. The use of OCs to treat acne has been well established in open-label studies, comparative studies, and, most importantly, in placebo-controlled trials. Some of the more recent studies demonstrated improvements in acne with low-dose formulations of OCs in randomized, placebocontrolled, double-blind trials [4,6]. The objective of this article is to review data from clinical trials of various T Corresponding author. Tel.: +43 1 40400 2816. E-mail address: johannes.huber@meduniwien.ac.at (J. Huber). designs that demonstrate the efficacy of OCs in treating acne, with a focus on the trend toward treating acne with OCs containing low doses of hormones as shown in placebo-controlled trials. 2. Open-label and comparative trials Beginning in the early 1980s, several open-label studies have shown that OCs reduce the incidence of acne and the number of acne lesions. These studies also demonstrated improvements in acne as rated by the subjects and lower severity of acne grades. 2.1. Uncontrolled, open-label clinical studies Collectively, the studies of various OC regimens described here observed a marked reduction in incidence of acne as well as an improvement in acne with a low incidence of new-onset acne. In a 2-year multinational trial, Upton [7] reported a 96% decrease in acne incidence (from 11.0% to 0.4%) in 2947 women treated with a triphasic OC [30-40-30 Ag ethinyl estradiol (EE)/50-75-125 Ag levonorgestrel (LNG); TriphasilR, Wyeth Pharmaceuticals, Collegeville, PA, USA]. The incidence rates of both acne and seborrhea were also reduced with a monophasic OC containing desogestrel (DSG) (30 Ag EE/150 Ag desogestrel; DesogenR, Organon, Roseland, NJ, USA/MarvelonR, Organon, Oss, The Netherlands) [8]. After six cycles of 0010-7824/$ see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2005.07.010

24 J. Huber, K. Walch / Contraception 73 (2006) 23 29 treatment, preexisting acne had disappeared in N80% of the 1021 women who had acne at baseline [8]. In a large European multicenter trial of more than 40,000 women using a monophasic OC [35 Ag EE/250 Ag norgestimate (NGM); Ortho CyclenR, Ortho-McNeil Pharmaceuticals, Raritan, NJ, USA; CilestR, Janssen-Cilag, High Wycombe, Bucks, UK] for six cycles, only 1% experienced new onset of acne or worsening of existing acne [9]. Of the 5086 women who had acne at baseline, 38% reported improvement [9]. In a study that evaluated the effects of the triphasic OC containing 30-40-30 Ag EE/50-75-125 Ag LNG on acne, the incidence of pustular acne decreased from 18% to 9%, and the incidence of papulopustular acne decreased from 35% to 15% after up to 11 months of therapy [10]. Acne was eradicated in 31% of women in the study (n = 271) [10]. Moreover, based on patient assessments, more than three quarters of the participants reported that their acne had improved, while 22% reported no change and only 2% believed their acne had worsened [10]. In Germany, a large study (n =2280) evaluated a multiphasic OC containing DSG (40 Ag EE/25 Ag DSG for 7 days, 30 Ag EE/125 Ag DSG for 15 days, pill-free interval for 6 days) [11]. Among the 592 women with acne at enrollment in the study, acne disappeared in 37% after three cycles of treatment [11]. Furthermore, acne severity was reduced among the women with acne [11]. Prilepskaya et al. [12] investigated the effects of a triphasic regimen of DSG (35-30-30 Ag EE/50-100-150 Ag DSG; Tri-merciR; Organon) on the skin of women (n =57) with facial seborrhea and mild or moderate acne. Severity of acne significantly declined after three and six treatment cycles compared with baseline (pb.01 and pb.0001, respectively) [12]. These improvements were accompanied by significant increases in self-esteem and self-confidence. Similarly, Falsetti [13] evaluated a biphasic DSG formulation given to 30 women with acne for nine cycles and found a progressive improvement in acne in all patients. Open-label clinical trials have also shown a reduction in preexisting acne lesions with OCs. After 6 months of therapy, acne counts declined and papules and pustules were reduced in 10 patients treated with a triphasic OC (35 Ag EE/180-216-250 Ag NGM, VivelleR, Janssen-Cilag) [14]. In a small study (n =41) with another triphasic OC (30-40- 30 Ag EE/50-75-125 Ag dl-norgestrel), Lemay et al. [2] reported an 80% decrease in the number of comedones in 69% of the patients after 6 months of therapy. Similarly, gestodene (GSD) was effective in a study of 21 women with mild to moderate acne [15]. The triphasic OC containing 30-40-30 Ag EE/50-70-100 Ag GSD (Tri-MinuletR; Wyeth Pharmaceuticals) decreased the mean total lesion count from baseline after 13 cycles [15]. In addition, the mean overall severity of acne grade was reduced and a trend toward reduction of sebum production was observed [15]. Assessments by both investigators and patients demonstrated significant (p b.001) improvements after treatment [15]. Women with greasy skin disorders (n =7985) likewise experienced a dramatic reduction in symptoms after six cycles of treatment with an OC containing 30 Ag EE/2 mg dienogest (ValetteR; Jenapharm, Jena, Germany) [16]. Selfassessments indicated that the OC improved greasy skin disorders in 81% of the women [16]. Improvements were greatest in women with severe or moderate symptoms at baseline [16]. 2.2. Comparative trials with EE/cyproterone acetate The hormonal combination of 35 or 50 Ag EE with 2 mg cyproterone acetate (CPA) (DianeR; Schering, Berlin, Germany) has an approved indication in Europe for the treatment of acne and provides the added benefit of contraception. The effects of EE/CPA are well documented in the medical literature, including several studies that compared the effects of other OC formulations with EE/CPA. When 50 Ag EE/2 mg CPA was compared with an OC containing 50 Ag EE/1 mg norethisterone acetate (NETA) (Minovlar; Schering), the CPA formulation (n = 26) significantly decreased total and facial acne grades, papule and pustule counts, and sebum excretion compared with baseline, whereas EE/NETA (n =24) significantly lowered only acne grades and pustules [17]. In general, women treated with CPA had a more rapid and more complete response than those treated with NETA [17]. However, the only significant difference (p b.05) reported between the therapies was for acne grades [17]. Two studies compared EE/CPA and EE/LNG OC formulations [18,19]. Carlborg [18] reported that after six cycles, acne lesions were reduced by an average of 70% with 50 Ag EE/2 mg CPA (n =45) and by 72% with 35 Ag EE/2 mg CPA (n =44), but by only 35% with 30 Ag EE/150 Ag LNG (LevlenR, NeovlettaR, MicrogynonR; Schering) (n = 36), which was a statistically significant difference between treatments (p b.0001). In a comparative study of 50 Ag EE/2 mg CPA (n =10) and the triphasic OC containing 30-40-30 Ag EE/50-75-125 Ag LNG (n = 10), patients in each group had similar reductions of approximately 90% in acne counts and severity after 6 months of therapy [19]. Other comparative studies evaluating the effects on acne of EE/CPA and OC regimens containing EE/DSG have shown that both treatments improved acne; however, statistical significance for between-group comparisons varied among the studies [20 23]. Erkkola et al. [20] compared the effect of 35 Ag EE/2 mg CPA (n =83) with 30 Ag EE/150 Ag DSG (Marvelon) (n =79) for nine cycles and found that significantly more (p b.05) women treated with EE/CPA (81%) had improved facial acne than women treated with EE/DSG (63%). Vartiainen et al. [22] compared 35 Ag EE/2 mg CPA (n =84) and combiphasic 40 30 Ag EE/25 125 Ag DSG (GracialR; Organon) (n = 80) in a randomized, multicenter study. Both treatments significantly reduced (p V.003) the numbers of comedones, papules and pustules compared with baseline after three and six

J. Huber, K. Walch / Contraception 73 (2006) 23 29 25 treatment cycles [22]. However, reductions in nodules were also significant, except at Cycle 6 with EE/DSG [22]. No statistically significant differences between the therapies were noted [22]. Similar results were reported in a study of 50 Ag EE/2 mg CPA (n =39) and 30 Ag EE/150 Ag DSG (VarnolineR; Organon, Riom, France) (n = 30) in that both regimens produced comparable significant reductions in the number of acne lesions [23]. In a small study designed to compare the effects on acne of 50 Ag EE/2 mg CPA and 30 Ag EE/150 Ag DSG in women in Thailand, results differed between the two study sites [21]. At center A, the decrease in acne score from baseline did not reach statistical significance in women treated with DSG (n =14), but the score decreased significantly after three and six cycles (p b.05) in the group treated with EE/CPA (n =17) [21]. In addition, the groups differed significantly (pb.05) in the change in acne scores at Cycle 6 [21]. At center B, treatment with both preparations (n =15 for each group) resulted in a significant decrease in mean acne score after six cycles (pb.01 for DSG, pb.001 for CPA), and there was no significant difference between groups [21]. The authors noted that the small numbers of patients and differences in the acne rating methodology at the two centers may explain the inconsistent results [21]. More recently, 35 Ag EE/2 mg CPA (n =33) and 30 Ag EE/3 mg drospirenone (DRSP) (YasminR; Schering) (n =58) were found to significantly (p=.0006) reduce median lesion counts from baseline by 59% and 63%, respectively, after nine treatment cycles; differences between groups were not significant [24]. 2.3. Other comparative trials Other studies reported acne improvement with formulations containing similar EE doses but different progestins. Mango et al. [25] evaluated the effect of 30 Ag EE/75 Ag GSD (MinuletR) compared with 30 Ag EE/150 Ag DSG (Marvelon) in 19 women with acne. Treatment with both GSD (pb.02) and DSG (pb.05) for 9 months resulted in a similar significant decrease in mean acne scores from baseline, and no significant difference was reported between the OCs [25]. In two small studies comparing 30 Ag EE/150 Ag DSG with 30 Ag EE/150 Ag LNG, both formulations were effective in significantly reducing acne [26,27]. Palatsi et al. [26] reported significant reductions in acne severity from baseline with both 30 Ag EE/150 Ag DSG (Marvelon, pb.001) and 30 Ag EE/150 Ag LNG (Levlen/Neovletta/ Microgynon, Schering, p b.01). After six treatment cycles, women treated with EE/DSG had significantly better (pb.05) results than those treated with EE/LNG [26]. Using the same OC formulations, Rosen et al. [27] found that the reduction in mean acne lesion counts from baseline was significant for both groups (pb.02) after nine cycles, with no between-group differences. In a randomized, multicenter study comparing 30 Ag EE/150 Ag LNG (Levlen/Neovletta/Microgynon) with 30 Ag EE/2 mg chlormadinone acetate (CMA) (BelaraR; Grqnenthal, Aachen, Germany) for the treatment of acne, 59% of patients treated with EE/CMA (n =101) and 46% of those treated with EE/LNG (n =98) showed a reduction in papules and pustules of at least 50% after 12 cycles (EE/CMA vs. EE/LNG, p =.02) [5]. Both formulations also reduced comedonal acne of the face as well as acne of the décolleté and back after 12 cycles of therapy [5]. Moreover, 80% and 76% of the subjects taking EE/CMA and EE/LNG, respectively, had resolution of seborrhea after 12 cycles [5]. In a study of low-dose OCs, total acne lesions were significantly reduced after three cycles with both 20 Ag EE/100 Ag LNG (AlesseR/LoetteR, Wyeth Pharmaceuticals) (n = 27) and 20 Ag EE/1 mg NETA (LoestrinR; Parke-Davis, New York, NY) (n =25) as compared with baseline (pb.05 for each) [3]. Improvements from baseline in total inflammatory and noninflammatory lesions were also similar for both formulations [3]. More recently, Winkler et al. [28] reported a decrease in the number of subjects with more than 10 lesions for two 20-Ag OCs at Cycle 6 compared to baseline, one OC containing DSG (59 women vs. 16) and the other LNG (60 women vs. 17). A recent randomized, double-blind, noninferiority trial found that 30 Ag EE with DRSP (Yasmin) was more effective in reducing total lesion counts and had a better investigator s assessment of therapeutic effect on facial acne than 35 Ag EE with 180, 215, 250 NGM (Ortho Tri-Cyclen, Ortho-McNeil Pharmaceuticals; Tri-Cilest; Janssen-Cilag) [29]. Both formulations were equally effective in reducing inflammatory lesions [29]. 3. Placebo-controlled trials None of the aforementioned studies included a placebo group and, therefore, did not take into account the large placebo effect that is typical of acne studies. Many factors can contribute to this placebo effect, including the bregression to the meanq phenomenon and the careful skin-care procedures outlined by the study protocol [30,31]. Fortunately, rigorous, placebo-controlled studies investigating the effects of OCs on acne have been reported recently. Although the first placebo-controlled trials examining OCs for the treatment of acne used an OC containing 35 Ag EE with NGM, the most recent trials have demonstrated acne improvement with an OC containing the lower dose of 20 Ag EE with the lowest available dose of LNG in a combined OC. 3.1. Placebo-controlled trials with Ortho Tri-Cyclen/Tri-Cilest Placebo-controlled trials examining the effects of OCs on acne were first reported with the triphasic OC containing 35 Ag EE/180-215-250 Ag NGM (Ortho Tri-

26 J. Huber, K. Walch / Contraception 73 (2006) 23 29 Table 1 Study and patient characteristics in placebo-controlled, randomized, double-blind trials of OCs for acne Study Formulation/length of study Patient characteristics Study entry criteria Efficacy outcomes Redmond et al. [31], Lucky et al. [32] Maloney et al., 2001 [33] Thiboutot et al. [6], Leyden et al. [4] 35 Ag EE/180-215-250 Ag NGM for six cycles 20-30-35 Ag EE/1 mg NETA for six cycles 20 Ag EE/100 Ag LNG for six cycles Age: 15 49 years, generally healthy, moderate acne Age: 14 49 years, generally healthy, at least moderate acne Age: z 14 years, generally healthy, moderate acne 6 100 comedones, 10 50 papules or pustules, V 5 nodules 20 100 comedones, 20 65 papules or pustules, V5 nodules 6 200 comedones, 10 75 papules or pustules, V5 nodules Change in inflammatory and total lesion counts Investigator s global assessment of improvement Changes in total, inflammatory and noninflammatory lesion counts Investigator s facial acne global assessment Patient s self-assessment of acne improvement and quality of life Changes in total, inflammatory and noninflammatory lesion counts Clinician s global assessment score Patient s self-assessment Cyclen/Tri-Cilest) (Table 1) [31,32]. A total of 339 women were included in two separate multicenter, double-blind studies and randomized to receive either the OC or placebo for six cycles [31,32]. Facial acne lesions were evaluated at each of the nine visits, and investigator and patient global assessments were determined at the end of the study [31,32]. Redmond et al. [31] reported that improvement in acne was significantly better in the group treated with EE/NGM (n =84) than in the placebo group (n =80) for all primary efficacy measures (Table 2). The mean reduction in inflammatory lesions was 51% with the OC compared with 35% for placebo (p=.01); total lesions were reduced by a mean of 46% for the OC group compared with 34% for the placebo group (p =.001) [31]. In the study by Lucky et al. [32], which had a similar design, total and inflammatory lesions were reduced from baseline by a mean of 53% and 62%, respectively, with EE/NGM, compared with 27% and 39% with placebo (p=.0001 for each). Significant differences in total lesion counts were evident after treatment Cycle 3 in the study by Redmond et al. [31]. In contrast, the mean percentage decrease in lesion counts was not significant at Cycle 3 in the report by Lucky et al. [32], although differences were significant at Cycles 2, 4, 5 and 6. Both investigator and patient assessments indicated an improvement in acne with EE/NGM compared with placebo. In the study by Redmond et al. [31], clinicians believed that significantly more patients in the EE/NGM group (83%) than in the placebo group (63%) had improved acne (p=.001). Similarly, 94% were improved with EE/NGM compared with 65% with placebo in the Lucky et al. study (pb.001) [32]. Ethinyl estradiol/ norgestimate-treated patients (82%) were more likely than placebo-treated patients (48%) to rate themselves as improved at the end of the study by Redmond et al. [31] (p=.001); Lucky et al. [32] reported similar results (pb.001). 3.2. Placebo-controlled data with Estrostep Further placebo-controlled trials of OCs and acne evaluated an OC with a triphasic dose of EE. Maloney et al. [33] pooled and analyzed data from two studies investigating the effects of 20-30-35 Ag EE/1 mg NETA (Estrostep, Parke-Davis) on acne (Table 1). In these multicenter studies identical in design, ethnically diverse women with high baseline lesion counts were randomized to receive either triphasic EE/NETA (n =297) or placebo (n =296) for six cycles [33]. Primary efficacy endpoints were changes from baseline in acne lesion counts, the investigator s global assessment of facial acne and a patient self-assessment quality-of-life questionnaire specific to acne (Acne-QOL) [33]. At the end of the study, significant differences between EE/NETA and placebo were observed for mean total (p b.0001), inflammatory (p=.0004) and noninflammatory (p b.0001) lesion counts (Table 2) [33]. Ethinyl estradiol/ norgestimate was significantly better than placebo for total lesion counts starting at Cycle 3 [33]. The percentage changes from baseline with EE/NETA for total and inflammatory lesions were 43% and 50%, respectively, compared with 31% and 39% for placebo [33]. The investigator s facial acne global assessment indicated that a significantly higher percentage of women treated with EE/NETA had improvement after six cycles than those treated with placebo (p=.0004) [33]. Specifically, more EE/ NETA-treated patients (44%) than placebo-treated patients (30%) achieved a rating of absent, minimal or mild acne [33]. Patient assessments of improvement with EE/NETA were also significantly better (p b.0001) than with placebo

Table 2 Inflammatory and total acne lesion improvements with OCs in placebo-controlled, randomized, double-blind trials Study Redmond et al. [31] Lucky et al. [32] Population analyzed Lesion type Treatment group (n) Lesion counts, mean (FSD) Baseline Cycle 6 Change from baseline Percent decrease from baseline p value a EE b Inflammatory EE/NGM (84) 18.7 8.7 9.9 (9.3) 51.4.01 Placebo (80) 19.0 12.1 6.9 (9.9) 34.6 Total EE/NGM (84) 53.9 26.1 27.8 (24.2) 46.4.001 Placebo (80) 54.5 35.4 19.1 (21.1) 33.9 EEb Inflammatory EE/NGM (79) 19.4 7.7 11.8 (8.9) 62.0 (30.3).0001 Placebo (81) 20.0 12.4 7.6 (8.9) 38.6 (41.2) Total EE/NGM (79) 54.8 25.7 29.1 (22.8) 53.1 (29.9).0001 Placebo (81) 50.0 35.9 14.1 (23.6) 26.8 (43.7) Maloney ITT d Inflammatory EE/NETA (297) 30 15.0 15.0 50.0.0004 e et al. [33] c Placebo (296) 30 18.2 11.8 39.4 Total EE/NETA (297) 75 42.7 32.3 43.0 b.0001 e Placebo (296) 75 52.1 22.9 30.5 Thiboutot et al. [6] Leyden et al. [4] J. Huber, K. Walch / Contraception 73 (2006) 23 29 27 EEb Inflammatory EE/LNG (96) 19.9 (9.6) 9.5 (7.3) 10.4 (11.0) 46.8 (40.6).024 Placebo (105) 18.1 (9.1) 11.5 (8.9) 6.7 (10.4) 32.6 (48.4) Total EE/LNG (96) 58.7 (33.3) 33.9 (27.4) 25.2 (30.2) 39.9 (40.2).007 Placebo (105) 57.8 (33.9) 41.6 (29.4) 16.1 (31.8) 23.4 (46.2) ITT f Inflammatory EE/LNG (185) 21.8 (11.5) 13.6 (11.7) 8.1 (13.1) 31.6 (53.7).044 Placebo (186) 21.9 (11.1) 16.1 (14.4) 5.8 (14.0) 22.3 (50.2) Total EE/LNG (185) 72.0 (56.0) 57.3 (73.4) 14.7 (51.9) 22.8 (50.0).017 Placebo (186) 68.7 (46.9) 65.2 (72.4) 3.5 (47.0) 9.0 (54.9) EE= evaluable for efficacy; ITT=intention to treat. a p value for difference in mean change from baseline between OC and placebo groups, unless otherwise specified. b Defined as all women who completed the study without critical protocol violations. c Values for cycle 6 and change from baseline were extrapolated from the mean total and mean inflammatory lesion counts of the entire ITT population at baseline and the percent decrease from baseline reported by the authors. Baseline values are those reported for the entire ITT population. d Defined as all randomized subjects who received at least one dose of active drug following baseline acne examination. e p value for percent change from baseline between OC and placebo group. f Defined as all women who received study medication. for the self-perception, role-emotional, role-social and acne symptom domains of the Acne-QOL [33]. Among the women treated with EE/NETA, 84% considered their acne somewhat or much improved at study completion, compared with 65% of patients in the placebo group (pb.0001) [33]. Significantly more women taking EE/NETA (65%) than placebo (54%) said that they would recommend the treatment to others (p =.005) [33]. 3.3. Placebo-controlled trials with Alesse/Loette Two separate multicenter, randomized, double-blind trials with 20 Ag EE/100 Ag LNG (Alesse/Loette) demonstrated improvements in acne with the lowest dose of EE reported in placebo-controlled trials (Table 1) [4,6]. Each study compared the change from baseline in acne lesions as well as investigator and patient assessments of improvement in the appearance of acne [4,6]. Thiboutot et al. [6] found that numbers of total, inflammatory and noninflammatory lesions were significantly lower (p b.05) with EE/LNG as compared with placebo (Table 2). The mean percentage decreases from baseline at Cycle 6 for total and inflammatory lesions were 40% and 47% with EE/LNG (n = 96), respectively, compared with 23% and 33% with placebo (n =105) [6]. Leyden et al. [4] showed similar significant differences with treatment in the mean changes from baseline in total, inflammatory and noninflammatory lesions. At Cycle 6, the mean percentage changes for the EE/LNG and placebo groups were 23% and 9% for total lesions (pb.005), 32% and 22% for inflammatory lesions (p=.081, p=.0437 for change in lesion count), and 13% and 4% for noninflammatory lesions (p b.05) [4]. In both studies, the significant decreases in total lesions with EE/ LNG compared with placebo were apparent as early as Cycle 2 [4,6]. Investigator and patient self-assessments also indicated acne improvement in both studies with 20 Ag EE/100 Ag LNG. Thiboutot et al. [6] reported that clinicians rated significantly more subjects as clear or almost clear after receiving EE/LNG (58%) as compared with placebo (47%). Leyden et al. [4] reported similar results: 48% of women treated with EE/LNG were rated as clear or almost clear, compared with 38% of those treated with placebo. Patient self-assessments of treatment efficacy also indicated superiority of EE/LNG over placebo in both studies [4,6]. Among the women in the EE/LNG groups, 80% to 82% rated their acne as bimproved,q whereas 63% to 68% of the patients treated with placebo considered themselves improved [4,6]. Noteworthy is the large placebo effect observed in most acne trials, as well as those described herein. This may be explained in part by the trial protocols that include careful

28 J. Huber, K. Walch / Contraception 73 (2006) 23 29 skin care [30,31], as well as physician encouragement to comply with meticulous skin care practices. Acne also has a fluctuating clinical course that includes spontaneous improvement in some women [30,31]. Finally, many dermatologists attribute the large placebo effect to investigator and patient optimism. The clinical significance of progestin androgenicity, specifically that of LNG, with OC use is controversial. However, the fact that combined OCs decrease the incidence and symptoms of acne demonstrates that OCs containing a progestin and estrogen are not androgenic, no matter which progestin is used. Two studies with 20 Ag EE/100 Ag LNG found that this OC significantly decreased bioavailable testosterone and other androgens [3,4], supporting the lack of androgenicity of this EE/LNG OC. 4. Conclusions A number of published clinical trials have clearly demonstrated that OCs are an effective means to treat acne in women. Rigorous placebo-controlled trials support the data from previous open-label and comparative studies, showing that OCs have a beneficial effect on mild to moderate acne. Moreover, improvement in acne can have a positive impact on health-related quality of life, including an improved perception of self. The most recent placebo-controlled trials have demonstrated that the lowest effective dose of EE in a monophasic OC shown to reduce acne lesions is 20 Ag. The fact that the efficacy of EE/LNG, EE/NETA and EE/NGM OCs was compared in different studies, as well as their different progestin types and estrogen doses, makes it difficult to compare their efficacy all are effective for the treatment of acne. The World Health Organization and others have recommended using the lowest effective dose of hormonal oral contraception to reduce potential risk, avoid nuisance side effects and improve patient compliance [34 36]. Nuisance side effects that may accompany OC use, including nausea, bloating and breast tenderness, have been shown to be significantly lower with OCs containing 20 Ag than those containing 35 Ag [37]. The effectiveness of a low-dose OC in the treatment of acne should facilitate the initiation of OCs with the lowest effective hormonal dose. Acknowledgments The authors would like to thank Kathleen Ohleth, Ph.D., for collaborating on the preparation of the manuscript. Wyeth Pharmaceuticals provided support to the medical writer (KO) for writing services. References [1] Thiboutot D. New treatments and therapeutic strategies for acne. Arch Fam Med 2000;9:179 87. [2] Lemay A, Dewailly SD, Grenier R, Huard J. Attenuation of mild hyperandrogenic activity in postpubertal acne by a triphasic oral contraceptive containing low doses of ethynyl estradiol and d,lnorgestrel. J Clin Endocrinol Metab 1990;71:8 14. [3] Thorneycroft IH, Stanczyk FZ, Bradshaw KD, Ballagh SA, Nichols M, Weber ME. 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