J.K.L. Tan, MDa and H. Degreef, MD, PhDb
aAcne Research & Treatment Center, Windsor, Ontario, University of Leuven, Leuven, Belgium
Oral contraceptives (OCs) can reduce acne by lowering the production of adrenal and ovarian androgens, by inhibiting 5- alpha-reductase, which in turn, reduces the levels of dihydrotestosterone, and by stimulating sex hormone binding globulin (SHBG), thus reducing the levels of free testosterone. In newer OCs, such as Tricyclen and Diane-35, the progestin component is minimally androgenic and anti-androgenic respectively, thereby enhancing the favorable profile of these products in the treatment of hyperandrogenic disorders, including acne. The efficacy of these agents and their long-term safety profile supports their use in various grades of acne in females:
- as adjunctive therapy to topical agents for women with mild non-scarring acne desiring oral contraception
- as primary therapy for patients with moderate non-scarring acne in combination with topical therapy and systemic antibiotics
- as one of two preferred methods of contraception in patients with scarring and severe inflammatory acne being treated with systemic isotretinoin
acne, oral contraceptives, progestin
Acne is initiated by the effect of androgens on pilosebaceous units resulting in sebaceous hypersecretion and follicular occlusion. Hormonal therapy in acne is, therefore, rationally directed at interrupting this initial phase in the sequence of acne pathogenesis.
Oral contraceptives have been available since 1960, and have evolved to contain less estrogen, thus minimizing the risk of thromboembolic events, hepatic tumors, hypertension, and altered glucose metabolism. As well, present day OCs include progestins, which have less intrinsic androgenicity. These developments in OC pharmacology also led to their usefulness in treatment across the spectrum of acne severity in females.1
Hormonal Pathways in Acne Pathogenesis
Androgens that are relevant in acne pathogenesis include dihydrotestosterone (DHT), testosterone (T), androstenedione (A) and dehydroepiandrosterone-sulfate (DHEA-S). The production of these androgens from ovaries and adrenal glands is mediated by gonadotrophins. Testosterone is converted to the biologically more potent 5-dihydrotestosterone (5-DHT) by 5-alpha-reductase. The bioavailable testosterone fraction is considered to be biologically active and comprises the free fraction of testosterone and the fraction bound by albumin. Levels of free testosterone are inversely related to levels of sex hormone binding globulin (SHBG).
OCs, which contain estrogen and progestins, directly affect androgen physiology and can therefore impact acne. Potential mechanisms of the therapeutic effect of estrogens include:
- decreased production of adrenal (DHEA-S) and ovarian androgens (A, T)
- inhibition of 5-alpha-reductase leading to the reduction of DHT levels
- stimulation of SHBG, reducing levels of free T
|19-nortestosterone derivatives Gonanes (norgestrel related)||Estranes (norethindrone related)||Progesterone derivatives|
Table 1: Overview of Progestins
Progestins vary in their androgenic potential and may therefore have variable effects on acne. The most commonly used progestins in OCs are 19-nortestosterone derivatives (see Table 1).2 Progestins with the lowest androgenic potential (e.g., desogestrel, norgestimeate, cyproterone acetate) are more appropriate in the treatment of acne and other hyperandrogenic disoders.
Hormonal Preparations Approved for Treatment of Acne
- Ethinyl estradiol 0.035mg with norgestimate in increasing doses of 0.180mg/0.215mg/0.250mg (Tricyclen):
Norgestimate has low intrinsic androgenicity with low binding affinity for androgen receptors, whereas it is strongly selective and avidly bound to progesterone receptor sites. Two 6-month, randomized, double-blind placebo-controlled trials involving 507 females with moderate acne showed clinically and statistically significant reduction of inflammatory lesions and total lesion counts.3,4 Moderate acne was defined as 6-100 comedones, 10-50 papules or pustules, and no more than 5 nodules. The mean decrease in inflammatory lesion count was 12, or 62% from baseline (compared to 8 lesions or 39% for placebo), and the decrease in total lesion count was 29, or 53% (compared to 14, or 27% in placebo). No significant changes for nodules were noted. A 50% reduction in total lesion count was attained between the 4th to 6th month of treatment, with a plateau of effect attained at 6 months.
|Erkkola et. al (1990)12||Aydinlik et. al (1990)13||Gollnick et. al. (1998)14|
Compared to desogestrel/ethinyl estradiol*
|Standard Dermatological Assessment and Outcome Endpoints||No
|Yes: Lesion counts and acne
|Sample Size At Start/At Completion||162/133||1161/1071 (after 6 months);
850 (after 12 months);
192 (after 36 months)
|Duration of Treatment||9 months||Maximum 36 months||6 months|
|Efficacy||Complete healing: 60%
72% (at 6 months);
90% (at 12 months)
|Lesion count reduction 73%;
reduction in acne grade in 64%
|Adverse Events||Headache (7%), nausea (5%), breast tension (13%), melasma (7%)||Breast tenderness (12%), headache (9%), nausea (6%), nervousness (4%), dizziness(3%)|
Table 2: Summary of Pivotal Studies for Diane-35
* desogestrel 0.15 mg with ethinyl estradiol 0.03 mg
- Ethinyl estradiol 0.035mg and cyproterone acetate 2mg (Diane-35):
Cyproterone acetate (CPA) is an analogue of hydroxyprogesterone and has progestational activity. It acts as a potent antiandrogen by competitive inhibition of T and DHT binding to the androgen receptors, and by inhibiting gonadotropin secretion. It is currently available in a dose of 2mg CPA in combination with ethinyl estradiol (Diane-35). Higher doses of CPA (50-100mg/d) may be required in treatment of more refractory acne or if associated with hyperandrogenization.5
The effectiveness of Diane-50 (containing 0.05mg of ethinyl estradiol and 2mg of CPA) for the treatment of acne has been demonstrated in placebo-controlled and antibiotic-comparative trials. Two randomized controlled trials compared Diane-50 to systemic antibiotics in the treatment of acne. In a 6-month trial of 78 patients randomized to minocycline 50mg po bid or Diane-35, papules were reduced by 73% and 70%, and pustules by 77% and 83%, respectively.6 A similar 6-month trial evaluating Diane- 50 compared to tetracycline 500mg po bid in 92 women showed reduction in lesion counts of 74% and 68% respectively7.
Two randomized controlled trials compared Diane-35 to Diane- 50, one for 9 months and the other for 12 months. They demonstrated that these preparations were similarly effective in the treatment of acne.8,9 In a 6-month study of 133 patients randomized to treatment with Diane-35, Diane-50 or levonorgestrel 0.15mg/ethinyl estradiol 30mg, the reduction in acne lesions from baseline was 72%, 70%, and 35% respectively.10
The three pivotal studies referred to in the Canadian product monograph11 for Diane-35 are summarized in Table 2.12-14 One trial was randomized, comparing Diane-35 to desogestrel 0.15 mg/ethinyl estradiol 0.03mg, but was unblinded, introducing the potential for observer or patient bias. Standard dermatological outcome parameters for acne, such as lesional counts or change in acne grade, were used in only one study. In that study fifty percent reduction in lesion counts was attained between the 2nd to 4th month of treatment.14 Two studies used non-standard, subjective outcome parameters such as “healing/improvement”, “complete healing” and “definitive healing” which are of limited utility in outcome assessment across studies.
Currently available OCs such as Tricyclen and Diane-35, containing progestins with minimal androgenic and antiandrogenic potential respectively, provide an important therapeutic option for women with acne. Their proven efficacy and long-term safety profile support their use for various grades of acne in females.
- Maddin WS, Landells I, Poulin Y, et al. Treatment of acne vulgaris and prevention of acne scarring: Canadian Consensus Guidelines. J Cutan Med Surg, 4(Supp 1):S4-2 – S4-13 (2000 Jun).
- Kuhl H. Progestagene zur empfangnisverhutung. Wien Med Wochenschr 137(18-19):433-40 (1987 Oct).
- Lucky AW, Henderson TA, Olson WH, Robisch DM, Lebwohl M, Swinyer LJ. Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris. J Am Acad Dermatol 37(5 Pt 1):746-54 (1997 Nov).
- Redmond GP, Olson WH, Lippman JS, Kafrissen ME, Jones TM, Jorizzo JL. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial. Obstet Gynecol 89(4):615-22 (1997 Apr).
- Beylot C, Doutre MS, Beylot-Barry M. Oral contraceptives and cyproterone acetate in female acne treatment. Dermatology 196(1):148-52 (1998).
- Monk BF, Almeyda JA, Caldwell IW, et al. Efficacy of low-dose cyproterone acetate compared with minocycline in the treatment of acne vulgaris. Clin Exp Dermatol 12(5):319-22 (1987 Sep).
- Greenwood R, Brummit L, Burke B, Cunliffe WJ. Acne: double blind clinical and laboratory trial of tetracycline, oestrogen-cyproterone acetate, and combined treatment. Br Med J 291(6504):1231-5 (1985 Nov).
- Colver GB, Mortimer PS, Dawber RP. Cyproterone acetate and two doses of oestrogen in female acne; a double-blind comparison. Br J Dermatol 118(1):95-9 (1988 Jan).
- Fugere P, Percival-Smith RK, Lussier-Cacan S, Davignon J, Farquhar D. Cyproterone acetate/ethinyl estradiol in the treatment of acne. A comparative dose-response study of the estrogen component. Contraception 42(2):225-34 (1990 Aug).
- Carlborg L. Cyproterone acetate versus levonorgestrel combined with ethinyl estradiol in the treatment of acne. Results of a multicentre study. Acta Obstet Gynecol Scand Suppl 134:29-32 (1986).
- Diane-35, product monograph, Berlex Canada.
- Erkkola R, Hirvonen E, Luikku J, Lumme R, Mannikko H, Aydinlik S. Ovulation inhibitors containing cyproterone acetate or desogestrel in the treatment of hyperandrogenic symptoms. Acta Obstet Gynecol Scand 69(1):61-5 (1990).
- Aydinlik S, Kaufman J, Lachnit-Fixson U, Lehnert J. Long-term therapy of signs of androgenisation with a low-dosed antiandrogen-oestrogen combination. Clin Trials J 27(6):392-402 (1990).
- Gollnick H, Albring M, Brill K. The efficacy of oral cyproterone acetate in combination with ethinyloestradiol in acne tarda of the facial type. J Dermatol Treat 9:71-79 (1998).