Combined oral contraceptive pills for treatment of acne
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The review will examine whether any COC is more effective than other COCs, oral or topical anti‐acne medications or placebo in the treatment of facial acne in women. We will evaluate the following hypotheses:
1) COC treatment for facial acne in females is more effective than no treatment or placebo in reducing the severity of facial acne.
2) COCs do not differ in their efficacy and are not more efficacious than other oral or topical anti‐acne medications in reducing the severity of facial acne.
3) COCs do not differ in discontinuation due to side effects.
Background
Acne vulgaris is a skin disorder of the sebaceous follicles that presents as lesions that are either inflamed (i.e., papules, pustules and nodules) or non‐inflamed (i.e., open or closed comedones, papules, pustules and nodules) (Toyoda 2001). It is one of the most common skin conditions requiring medical treatment, yet its pathophysiology is poorly understood. The characteristic localization of acne to the face and upper trunk is a result of the distribution of oil‐secreting structures known as sebaceous glands within the hair follicles. Although the etiology of acne involves a number of interrelated factors, a large amount of evidence implicates an increased rate of sebum production, which is predominantly controlled by androgenic sex hormones.
Globally, acne affects 79% to 95% of the adolescent population, 40% to 50% of men and women between 25 and 40 years of age and about 12% of women and 3% of men older than 40 years (Cordain 2002). In the United States alone, about 45 million people are affected by acne, with a prevalence of approximately 85% in the population 15‐24 years of age (White 1998). Acne is more common and more severe in young men who by the age of 25 years tend to have their acne resolved while the disease persists in women up until 40 years of age (White 1998). More than 25% of acne sufferers in the US consult a physician annually (Bergfeld 1995). In addition to the morbidity associated with lesions and adverse effects of treatments, acne can produce life‐long physical and emotional scars (Baldwin 2002). The cost of acne treatment constitutes an economic burden to both the individual and community.
No consensus exists as to the most appropriate approach to the management of acne. Individual acne lesions can remit spontaneously by unknown mechanisms that may be associated with de‐differentiation of follicular cells that produce sebum or by spontaneous resolution of inflammatory changes in the lesions (Downie 2002). Although effective prescribed medications are available, many women rely on over‐the‐counter preparations and herbal remedies, in conjunction with strict skin hygiene routines and dietary modifications (Webster 2002). Treatment options generally target one or more of the factors implicated in acne pathogenesis (i.e. blockage of hair follicle openings, bacteria colonization, abnormal keratinization or excess sebum production). Medications that affect one or more of these mechanisms either alone or in combination are commonly used (Eady 1994; Leyden 1997; Burkhart 2000; Thiboutot 2000; Webster 2002).
Combined oral contraceptives (COCs) reduce the risk of acne through several mechanisms. First, COCs appear to decrease free testosterone levels by 40 to 50 percent, on average (Fotherby 1994; Thorneycroft 1999). This is due to a reduced production of the androgen, testosterone, achieved by the suppression of luteinizing hormone, which causes decreased androgen synthesis. Androgen bioavailability is also reduced when COCs increase the level of the protein that binds free androgens (sex hormone‐binding globulin), which in turn, increases binding of testosterone. Testosterone has to be converted in the hair follicles and skin to dihydrotestosterone by the enzyme 5‐alpha reductase to lead to acne (Cassidenti 1991). COCs prevent this conversion of free testosterone to dihydrotestosterone by blocking androgen receptors and inhibiting 5‐alpha‐reductase activity. Progestin types appear to differ in the degree to which they prevent testosterone production, bioavailability, or conversion (Rabe 2000).
A number of COCs (containing different progestins and hormonal dosages) are prescribed for women with acne, often for their dual functions of acne treatment and contraception prevention. COCs traditionally used for acne treatment, though, have contained cyproterone acetate (CPA) and ethinyl estradiol (EE). In the UK, for example, the COC containing CPA 2 mg and EE 35 mcg is licensed for treatment of women whose acne is refractory to treatment with antibiotics (Seaman 2003). A drawback to the use of COCs is the occurrence of drug‐related adverse events, such as nausea, vomiting, breast tenderness, headache and menstrual disturbances, which can hinder adherence to the treatment regimen (Archer 1999; DelConte 1999; Parkin 2000). This review aims to determine the efficacy and discontinuation due to adverse effects of COCs used in the treatment of facial acne.
Objectives
The review will examine whether any COC is more effective than other COCs, oral or topical anti‐acne medications or placebo in the treatment of facial acne in women. We will evaluate the following hypotheses:
1) COC treatment for facial acne in females is more effective than no treatment or placebo in reducing the severity of facial acne.
2) COCs do not differ in their efficacy and are not more efficacious than other oral or topical anti‐acne medications in reducing the severity of facial acne.
3) COCs do not differ in discontinuation due to side effects.
Methods
Criteria for considering studies for this review
Types of studies
All randomized controlled trials reported in any language. Trials described as randomized by the authors but in which the method of randomization is uncertain will be noted and included.
Types of participants
Women of any age for whom facial acne vulgaris was assessed.
Types of interventions
Any COC compared to a second COC, oral or topical anti‐acne medication, no treatment or placebo. The COC treatment group also can include concomitant acne treatment.
Types of outcome measures
Trials must report on the effectiveness of drug treatment using at least one of the following outcomes:
a) change in specific types of facial lesion (i.e. open or closed comedones, papules, pustules or nodules) counts from baseline to last available evaluation or specific facial lesion counts at the last available evaluation;
b) change in total facial lesion counts from baseline to last available evaluation or the total facial lesion counts at the last available evaluation;
c) global assessments made by the clinician or the participant regarding improvement in skin condition (e.g. excellent, good or fair progress versus no change or worse);
d) psychosocial function outcomes, such as quality of life and disability indices, and utility outcome (e.g. willingness to pay or accept treatment); and
e) early study discontinuation due to adverse events, including worsening of acne.
Search methods for identification of studies
We will search the computerized databases Cochrane Skin Group trial register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE using PubMed, EMBASE, POPLINE, Biological Abstracts and LILACS for randomized controlled trials of COCs.
We also will assess the reference lists of published reports and seek information from colleagues on unpublished trials, technical reports, conference proceedings and dissertations. Other experts and pharmaceutical companies with an interest in this topic will be contacted for relevant published or unpublished reports. We will write to the corresponding author of each included trial to inquire about any published or unpublished trials we might have missed.
We will search the Cochrane Skin Group's trial register using the strategy:
Acne*
We will search CENTRAL using the strategy:
(acne or acne vulgaris) and (contraceptives, oral or contracept* or ((cyproterone acetate or desogestrel or ethinodiol diacetate or gestodene or levonorgestrel or lynestrenol or norethindrone or norethisterone or norethynodrel or norgestimate) and ethinyl estradiol) and (clinical trial or controlled study or randomised controlled study or randomized controlled trial))
We will perform the PubMed search of MEDLINE with the Cochrane search strategy revised for PubMed searches (Robinson 2002):
((randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double‐blind method [mh] OR single‐blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR ("latin square" [tw]) OR placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow‐up studies [mh] OR prospective studies [mh] OR cross‐over studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animal [mh] NOT human [mh])) AND ((contraceptives, oral OR ((cyproterone acetate OR desogestrel OR ethinodiol diacetate OR gestodene OR levonorgestrel OR lynestrenol OR norethindrone OR norethynodrel OR norgestimate) AND ethinyl estradiol)) AND (acne OR acne vulgaris))
We will search EMBASE using the strategy:
((acne OR acne vulgaris) AND (oral contraceptive agent OR ((cyproterone acetate OR desogestrel OR ethinodiol diacetate OR gestodene OR levonorgestrel OR lynestrenol OR norethindrone OR norethynodrel OR norgestimate) AND ethinyl estradiol))) AND (clinical trial OR controlled study OR randomized controlled trial OR controlled(w)clinical(w)trial? OR random(w)allocation OR multi‐center study OR comparative(w)study OR evidence(w)based(w)medicine OR research(w)design OR double(w)blind(w)procedure OR single(w)blind(w)procedure OR random)
We will search POPLINE using the strategy:
(oral contraceptives / contraceptive agents / female / ((cyproterone acetate / desogestrel / ethinodiol diacetate / gestodene / levonorgestrel / lynestrenol / norethindrone / norethynodrel / norgestimate) & ethinyl estradiol)) & (acne / acne vulgaris)
We will search Biological Abstracts using the strategy:
(acne or acne*) and oral contraceptives or ((cyproterone acetate or desogestrel or ethinodiol diacetate or gestodene or levonorgestrel or norethindrone or norethynodrel or norgestimate or lynestrenol) and estradiol)
We will search LILACS using the strategy:
((cyproterone acetate or desogestrel or ethinylestrenol or gestodene or levanogestrel or levonorgestrel or linestrenol or lynestrenol or norethindrone or norethynodrel or noretinodrel or norgestimate) and (ethinyl estradiol or etinilestradiol or etinil estradiol) or (contraceptives, oral or anticonceptivos orales or anticoncepcionais orais)) and (acne or acnevulgaris or acne vulgar)
Data collection and analysis
The primary reviewer will assess all titles and abstracts located in the literature searches to determine their relevance to the objective of the review. Translators will be used for potentially eligible studies written in non‐English languages. Information will be extracted from each included trial about method of randomization, allocation concealment, blinding, pre‐treatment washout periods, types of intervention, participant characteristics, premature withdrawals from the trial and outcome measures.
All data will be entered and analyzed with RevMan 4.2. For trials that included two or more intervention groups, regardless of whether the authors identified a control group, we will make all possible comparisons between groups. Two reviewers independently will extract data from the studies identified for inclusion onto data extraction forms. The reviewers will not be blinded to the authors, journals or institutions. They also will assess the quality of each trial and determined its methodological strengths and weaknesses. These will be based on adequacy of sample size, randomization protocol, allocation concealment, inclusion and exclusion criteria, blinding, method of analysis and the extent of early discontinuation and loss‐to‐follow‐up. All discrepancies will be resolved by discussion. We will write to the corresponding authors for clarification or additional data as required.
We will calculate the number of events for any outcomes that were published as percentages if the absolute numbers for the numerators or denominators were provided. For continuous data, we will extract the means and standard deviation or standard error and calculate the weighted mean difference (WMD) and 95% confidence interval (95%CI). For dichotomous data, we will calculate the Peto odds ratio (OR) and 95% CI. We will combine results of different trials with similar types of interventions (i.e. same progestin type and dose, estrogen dose, and number of treatment cycles) in meta‐analysis to calculate a weighted treatment effect across trials.
