
A. Lemay, MD, PhDa and R. G. Langley, MD, FRCPCb
aEndocrinologie de la reproduction, Hôpital St-François d’Assise, Département d’Obstétrique et Gynécologie, Université Laval, Québec, Canada
bDivision of Dermatology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
ABSTRACT
There is compelling evidence that oral contraceptives (OCs) are effective in the management of mild-moderate acne vulgaris, as well as cumulative evidence that elevated levels of androgens in acne patients, relative to appropriate controls, are an underlying pathophysiological factor in acne. All low dose OCs reduce serum free testosterone (T) to a similar extent, which is contrary to the traditional concept that a patient who has acne should not use an OC containing a progestin with androgenic properties. The efficacy of various OCs to improve acne has been reported in transverse, cohort and comparative studies, and more recently in multicenter, randomized, placebo-controlled trials. Recently, an ultra-low dose OC (Alesse®, Wyeth) was shown to effectively reduce non-inflammatory and inflammatory lesions in mild-to-moderate acne, while having a profile of side-effects similar to that of a placebo. Besides its contraceptive efficacy, an ultra-low dose OC represents an attractive alternative as a single or associated medication in the management of acne.
Key Words:
acne, androgens, anti-androgens, antibiotics, oral contraceptives
An ultra-low dose oral contraceptive (Alesse®, Wyeth) containing 20µg ethinyl estradiol (EE) and 100mg levonorgestrel (LNG) was approved by TPP Canada for the treatment of mild-to-moderate acne in January 2002.1,2 Its contraceptive efficacy has been corroborated by ultrasonic evaluation of the ovaries showing inhibition of follicular development, and by hormonal measurements demonstrating suppression of estradiol and progesterone.3 It provides menstrual cycle control and tolerability that is equivalent to that of OCs containing 35µg of EE.4
Excess Androgens in Acne
A common notion is that neither acne vulgaris nor idiopathic hirsutism is associated with high serum levels of androgens in the absence of other associated signs and symptoms of hyperandrogenism. The range of reference androgen values has been established in laboratories mainly to rule out a secreting tumor. There is no established stratification of normal ranges to estimate androgen values for benign androgen conditions such as acne, hirsutism and polycystic ovarian syndrome. In this context, many believe that serum androgens are not elevated in typical acne. However, when appropriate controls were used, androgens of adrenal or ovarian origin increased in women presenting with otherwise unexplained acne5-10 A recent study demonstrated that serum T levels in acne patients were at least twice the level of normal controls without acne.9 Dehydroepiandrosterone sulphate (DHEAS) was also found to be elevated in acne patients when compared to a control group.9 Recent data also showed no change in androgen metabolism (5α- reductase and 17β-hydroxysteroid dehydrogenase) in sebaceous glands between subjects with and without acne, providing evidence against possible local production of androgens in this condition.8 Thus, a relative increase in circulating ovarian and adrenal androgens appear to play a role in the pathophysiology of acne. The sebaceous gland, which is sensitive to androgens, and which is responsible for the associated seborrhea should be considered as an underlying pathophysiological component.
Anti-Androgenic Action of Oral Contraceptives
Traditionally, clinicians believed that a patient with acne should not use an OC containing a progestin with androgenic properties.11 Investigators have speculated that the androgenic effects of progestins evaluated in animal and in vitro systems may increase the likelihood of androgen-related side-effects, including acne and hirsutism. The evidence is to the contrary. The suppression of LH and FSH by OCs results in a decreased secretion of androstenedione and testosterone by theca cells in the ovary. Estrogen-progestin combinations also increase the level of sex hormone-binding globulin (SHBG), resulting in greater T binding and a reduction in free T. The use of an OC also causes a reduction in serum levels of ovarian and adrenal androstenedione, and of DHEAS, which originates exclusively from the adrenal glands. Thus, the use of an OC has complementary actions mainly to lower free T and the androgen precursors secreted by the ovaries and the adrenals. The decrease in androgen action is reflected by a diminution in 3 α-androstenediol–glucuronide, which is the cellular catabolite of DHT by the sebaceous gland among peripheral tissues sensitive to androgens.
Estrogen-progestin combinations differ somewhat in their efficacy to inhibit T production and to increase SHBG levels. However, the net effect is similar for free T, which decreases by 40-50% in the average woman. Direct comparisons between various OC formulations show that they all reduce free T to the same extent.12,13 Since free T is the ultimate effector of circulating androgens, all OCs have a similar potential for improving acne.
Clinical Trials
Several studies have recognized a lower incidence of acne while using different OCs.14-17 Five pilot studies have also reported a 50-80% improvement in comedone counts, as well as in the numbers of papules and pustules after a few cycles of OCs containing various doses of EE and various types of progestins.13,18-21 These observations have now been recently confirmed by four multicenter, randomized, placebo-controlled trials using a triphasic OC formulation containing 35µg EE and 180-215-250µg NGM (Tri- Cyclen®)22,23 and the low dose monophasic combination of 20µg EE and 100µg LNG (Alesse®).24,25
Two similar Phase III trials (see Table 1) were conducted involving 35µg EE/180-215-250µg NGM (Ortho Tri- Cyclen®) vs. placebo for 6 months of treatment.22,23 In the first study, 257 patients, aged 15 to 49 were randomized into a multi-center, double-blind, placebo-controlled trial if they had moderate acne (6-100 comedones, 10-50 inflammatory lesions, and fewer than 5 nodules). One hundred sixty patients completed the 6-month study in the efficacy evaluable population. The OC group showed a statistically significant improvement over the placebo group for all primary efficacy measures. The second trial included 250 women and the treatment group performed significantly better than the placebo group for all primary efficacy measures.22
The second series of clinical studies of OCs in acne involved the use of the lower estrogen OC, Alesse®.24,26 Two outpatient, multicenter, randomized, double blind, placebo-controlled trials following a similar protocol were conducted to determine the effects of 20µg EE and 100µg LNG (Alesse®) on the treatment of moderate acne. In the first study, healthy women, at least 14 years of age, with regular menstrual cycles and moderate facial acne were randomly assigned to receive the active treatment or placebo for 6 cycles. Inflammatory, noninflammatory, and total lesion counts at cycle 6 with 20µg EE and 100µg LNG (Alesse®) were significantly lower when compared to placebo. Patients in the OC group also had significantly better clinician global and patient self-assessment scores than those in the placebo group at cycle 6. Similar results were documented in the second trial with significant decreases in the mean inflammatory and total lesion counts after 6 cycles in the OC group compared to the placebo group.25 In a sub study, biochemical markers of androgenicity were also assessed. Compared to placebo, use of this low dose OC resulted in significant reductions in free and bioavailable testosterone, androstenedione, 3α- androstanediol glucuronide (3α-G), and increased levels of SHBG after 6 cycles.
Author | OC Studied | N | Number Inflammatory Lesions | Regression of Lesions | Subject’s Self-Assessment of Improvement | ||||||
OC | Placebo | P | OC | Placebo | P | OC | Placebo | P | |||
Redmond, et al22 | Ortho-Tricyclen® | 250 | 56.4% | 34.6% | 0.01 | 46.4% | 33.9% | 0.001 | 82.0% | 47.0% | 0.001 |
Lucky, et al23 | Ortho-Tricyclen® | 257 | 62.0 | 38.6% | 0.0001 | 53.0% | 26.8% | 0.0001 | 91.0% | 70.0% | 0.001 |
Thiboutot, et al24 | Alesse® | 350 | 46.8 | 32.6% | 0.027 | 39.9% | 23.4% | 0.004 | 88.0% | 73.0% | 0.05 |
Leyden, et al25 | Alesse® | 371 | 41.5 | 27.9% | 0.016 | 29.7% | 9.1% | 0.001 | 81.0% | 72.0% | 0.03 |
Table 1: Results of four Phase III Clinical Trials for OCs in the treatment of acne.
Placebo effects are commonly seen in dermatology trials, acne trials in particular. This can be explained in part by trial protocols that include careful skin-care (e.g., proper skin cleansing and avoidance of comedogenic skin-care products). Patient compliance with meticulous skin-care practices is encouraged by regular visits to trial investigators. Such skin care alone may have a positive effect on acne. Furthermore, acne is known to have a fluctuating course with regression to the mean over time in a given cohort of patients. Because of this, the trial period includes spontaneous improvement in some women and the resolution of some acne flares present at baseline. Finally, many dermatologists attribute the large placebo effect to investigator and patient optimism.
Efficacy and Safety of Alesse® in Acne
One very interesting aspect of these studies was the unique opportunity to compare the side-effects associated with an OC to those of a placebo. In the 20µg EE and 100µg LNG (Alesse®) acne studies, symptoms usually attributed to the estrogen and/or progestin components of an OC were not different from those observed during the use of the placebo. As seen in Table 2, the very low dose EE/LNG combination did not induce significant modifications in the incidence of weight gain, breast tenderness, nausea, vomiting, headache and migraine.26
OCs and anti-androgen agents
The estro-progestin combination Diane-35®, containing 35ug EE combined with 2mg cyproterone acetate, a progestin having direct anti-androgen effects, is known to be quite effective in the treatment of acne and hirsutism, although there is no Class I evidence (randomized, doubleblind, controlled studies) supporting the efficacy of this prediction.27 Several OC formulations have been compared to Diane-35® and found to be as effective or somewhat less effective than this anti-androgenic combination.28-33 However, comparisons were limited to 6 cycles of treatment and the side-effect profiles were not compared. Although there seems to be improvement of acne after treatment with the anti-androgen spironolactone (Aldactone®), the few studies done to date have been methodologically weak. There are, as yet, no reports for the treatment of acne using flutamide (Euflex®), a nonsteroidal androgen receptor antagonist, or finasteride (Proscar®, Propecia®), an inhibitor of the 5-α-reductase enzyme converting T into the more active compound dihydrotestosterone (DHT) within the sebaceous gland. In theory, the addition of an anti-androgen would be more effective in hirsutism than in acne, since excess androgens are the main causative factor in hirsutism, whereas other factors are involved in the pathophysiology of acne. In practice, prescribing an anti-androgen for women of reproductive age requires effective contraception to prevent the possible occurrence of fetal anomalies induced by a compound having direct anti-androgenic actions.
Adverse event | 20µg EE and 100µg LNG (Alesse®) % (n=349) | Placebo % (n=355) | P-value* |
Headache | 31.5 | 30.1 | 0.74 |
Migraine | 3.2 | 2.3 | 0.49 |
Nausea | 14.0 | 11.3 | 0.31 |
Vomiting | 2.6 | 1.7 | 0.44 |
Weight gain | 3.4 | 2.3 | 0.37 |
Breast pain | 4.6 | 3.1 | 0.33 |
Table 2: Alesse® vs. Placebo: frequency of adverse events commonly associated with OCs.
* Fisher’s exact.
Pooled data of intended to treat population.26
Concomitant Use of OC and Antibiotics in Acne
Several pharmacokinetic and pharmacodynamic studies indicate that the antibiotics currently prescribed for acne treatment do not modify serum concentrations of EE and of various progestins.34-38 They do not interfere with the suppression of gonadotropins (LH and FSH) and ovarian sex steroid hormones (estradiol and progesterone).35,36,39-41 According to a recent bulletin from the American College of Obstetrics and Gynecology, the anti-infective agents tetracycline, doxycycline, ampicillin, metronidazole and quinolones do not reduce steroid levels in OC users.42 In a recent review of available data, the Pearl Index (number of pregnancies per 1000 women years) during the concomitant use of antibiotics and various OCs in acne was established at 1.6, which favorably compares with the failure rate of users who have not taken antibiotics.43 However, these data have been estimated on rather small numbers. In one Australian study, 209 inadvertent pregnancies in oral contraceptive users were studied to determine the associated factors. Forty-eight of the 209 patients (23%) took an antibiotic in the last two cycles before conception and were included as one of several reasons for OC failure.44 Caution should be exerted and another effective contraceptive method should be used whenever a patient is taking other antibiotics or doses of antibiotics higher than those prescribed in the usual treatment of acne. The patient taking an antibiotic should also be told to use another effective contraceptive means in case she experiences diarrhea or breakthrough bleeding, which could then suggest decreased absorption or efficacy of the OC, or inadequate compliance.
Conclusion
Based on the multiple factors involved in the pathogenesis of acne and on the severity of lesions, choosing one of the various treatment approaches depends on the needs of the patient and on the objectives of the physician. Dermatologists most frequently prescribe agents to normalize dyskeratinization and to reduce the proliferation of P. acnes and inflammatory skin changes. Sebum production, which is sensitive to a mild elevation of androgens can be reduced by a low dose OC. Besides its contraceptive and other non-contraceptive benefits, a low dose OC has a side-effect profile similar to that of a placebo and has been determined to have significant efficacy in the treatment of mild-to-moderate acne. The effects of using an oral contraceptive are usually not seen in chemical practice for 3-6 cycles. The application of another acne treatment during treatment with an OC is actually done in regular practice, but has yet to be evaluated in clinical research studies.
References
- Archer DF, Maheux R, DelConte A, O’Brien FB. Anew low-dose monophasic combination oral contraceptive (Alesse) with levonorgestrel 100 micrograms and ethinyl estradiol 20 micrograms. North American Levonorgestrel Study Group (NALSG). Contraception 55(3):139-44 (1997 Mar).
- Archer DF, Maheux R, DelConte A, O’Brien FB. Efficacy and safety of a low-dose monophasic combination oral contraceptive containing 100 microg levonorgestrel and 20 microg ethinyl estradiol (Alesse). North American Levonorgestrel Study Group (NALSG). Am J Obstet Gynecol 181(5 Pt 2):39-44 (1999 Nov).
- Coney P, DelConte A. The effects on ovarian activity of a monophasic oral contraceptive with 100 microg levonorgestrel and 20 microg ethinyl estradiol. Am J Obstet Gynecol 181(5 Pt 2):53-8 (1999 Nov).
- Rosenberg MJ, Meyers A, Roy V. Efficacy, cycle control, and side-effects of low- and lower-dose oral contraceptives: a randomized trial of 20 micrograms and 35 micrograms estrogen preparations. Contraception 60(6):321-9 (1999 Dec).
- Ginsberg GS, Birnbaum MD, Rose LI. Androgen abnormalities in acne vulgaris. Acta Derm Venereol 61(5):431-4 (1981).
- Lucky AW, McGuire J, Rosenfield RL, Lucky PA, Rich BH. Plasma androgens in women with acne vulgaris. J Invest Dermatol 81(1):70-4 (1983 Jul).
- Marynick SP, Chakmakjian ZH, McCaffree DL, Herndon JH Jr. Androgen excess in cystic acne. N Engl J Med 308(17):981-6 (1983 Apr).
- Thiboutot D, Gilliland K, Light J, Lookingbill D. Androgen metabolism in sebaceous glands from subjects with and without acne. Arch Dermatol 135(9):1041-5 (1999 Sep).
- Ayala C, Steinberger E, Smith K, Rodriguez-Rigau L, Petak M. Serum testosterone levels and reference ranges in reproductive-age women. Endocr Pract 5(6):322-9 (1999).
- Slayden SM, Moran C, Sams WM, Jr., Boots LR, Azziz R. Hyperandrogenemia in patients presenting with acne. Fertil Steril 75(5):889-92 (2001 May).
- Olsen TG. Therapy of acne. Med Clin North Am 66(4):851-71 (1982 Jul).
- van der Vange N, Blankenstein MA, Kloosterboer H, Haspels A, Thijssen JH. Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone. Contraception 41(4):345-52 (1990 Apr).
- Thorneycroft IH, Stanczyk FZ, Bradshaw KD, Ballagh SA, Nichols M, Weber ME. Effect of low-dose oral contraceptives on androgenic markers and acne. Contraception 60(5):255-62 (1999 Nov).
- Upton V. Clinical Experience with the Triphasic Oral Contraceptive. Princeton, Amsterdam: Elstein M., 1982.
- Bilotta P, Favilli S. Clinical evaluation of a monophasic ethinylestradiol/desogestrel containing oral contraceptive. Arzneimitteiforschung 38(7):932-4 (1988 Jul).
- Anderson F. Selectivity and minimal androgenicity of norgestimate in monophasic and triphasic oral contraceptives. Acta Obstet Gynecol Scand Suppl 156:15-21 (1992).
- Weber-Diehl F, Unger R, Lachnit U. Triphasic combination of Ethinyl Estradiol and Gestodene. Long-term clinical trial. Contraception 46(1):19- 27 (1992 Jul).
- Loudon N, Biddell S. The effect of the Triphasic Oral Contraceptive on Acne Vulgaris: An Interim Report of an Open Multicenter Study. Princeton, Amsterdam: Elstein M, 1982.
- Palatsi R, Hirvensalo E, Liukko P, et al. Serum Total and Unbound Testosterone and Sex Hormone Binding Globulin (SHBG) in Female Acne Patients Treated with Two Different Oral Contraceptives. Acta Derm Venereol 64(6):517-23 (1984).
- Lemay A, Dodin-Dewailly S, Grenier R, Huard J. Attenuation of Mild Hyperandrogenic Activity in Postpubertal Acne by a Triphasic Oral Contraceptive Containing Low Doses of Ethinyl Estradiol and d,1- Norgestrel. J Clin Endrocrinol Metab 71(1):8-14 (1990 Jul).
- Mango D, Ricci S, Manna P, Miggiano GA, Serra GB. Clinical and hormonal effects of ethinylestradiol combined with gestodene and desogestrel in young women with acne vulgaris. Contraception 53(3):163- 70 (1996 Mar).
- 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).
- 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).
- Thiboutot D, Archer DF, Lemay A, Washenik K, Roberts J, Harrison DD. A randomized, controlled trial of a low-dose contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonorgestrel for acne treatment. Fertil Steril 76(3):461-8 (2001 Sep).
- Leyden JJ, Harrison D. Efficacy and safety of a low-dose oral contraceptive containing 20 µg/100 µg levonorgestrel for the treatment of acne: a randomized, placebo-controlled trial. At: the Annual Meeting of the American Academy of Dermatology, 2001 March, Washington, DC.
- Coney P, Washenik K, Langley RG, DiGiovanna JJ, Harrison DD. Weight change and adverse event incidence with a low-dose oral contraceptive: two randomized, placebo-controlled trials. Contraception 63(6):297-302 (2001 Jun).
- Aydinlik S, Kaufmann 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).
- Miller J, Wojnarowska F, Dowd P, et al. Anti-androgen treatment in women with acne: a controlled trial. Br J Dermatol 114(6):705-16 (1986 Jun).
- Carlborg L. Cyproterone acetate versus levonorgestrel combined with ethinyl estradiol in the treatment of acne. Results of a multicenter study. Acta Obstet Gynecol Scand Suppl 134:29-32 (1986).
- Levrier M, Degrelle H, Bestaux Y, Bourry-Moreno M, Brun J, Sailly F. Efficacité sur l’acné des contraceptifs oraux. Rev Fr Gynécol Obstét 83(7- 9):573-6 (1988 Jul).
- Erkkola R, Hirvonen E, Luikku J, Lumme R, Männikkö H, Aydinlik S. Ovulation inhibitors containing cyproterone acetate or desogestrel in the treatment of hyperandrogenic symptoms. Acta Obstet Gynecol Scand 6(1):61-5 (1990).
- Wishart JM. An open study of Triphasil and Diane 50 in the treatment of acne. Australas J Dermatol 32(1):51-4 (1991).
- Charoenvisal C, Thaipisuttikul Y, Pinjaroen S, et al. Effects on Acne of Two Oral Contraceptives Containing Desogestrel and Cyproterone Acetate. Int J Fertil Menopausal Stud 41(4):423-9 (1996 Jul-Aug).
- Joshi JV, Joshi UM, Sankholi GM, et al. A study of interaction of low-dose combination oral contraceptive with Ampicillin and Metronidazole. Contraception 22(6):643-52 (1980 Dec).
- Back DJ, Breckenridge AM, MacIver M, et al. The effects of ampicillin oral contraceptive steroids in women. Br J Clin Pharmacol 14(1):43-8 (1982 Jul).
- Back DJ, Tjia J, Martin C, et al. The lack of interaction between temafloxacin and combined oral contraceptive steroids. Contraception 43(4):317-23 (1991 Apr).
- Neely JL, Abate M, Swinker M, D’Angio R. The effect of doxycycline on serum levels of ethinyl estradiol, norethindrone, and endogenous progesterone. Obstet Gynecol 77(3):416-20 (1991 Mar).
- Murphy AA, Zacur HA, Charache P, Burkman RT. The effect of tetracycline on levels of oral contraceptives. Am J Obstet Gynecol 164(1 Pt 1):28-33 (1991 Jan).
- Friedman CI, Huneke AL, Kim MH, Powell J. The effect of ampicillin on oral contraceptive effectiveness. Obstet Gynecol 55(1):33-7 (1980 Jan).
- Maggiolo F, Puricelli G, Dottorini M, Caprioli S, Bianchi W, Suter F. The effect of ciprofloxacin on oral contraceptive steroid treatments. Drugs Exp Clin Res 17(9):451-4 (1991).
- Csemiczky G, Alvendal C, Landgren BM. Risk for ovulation in women taking a low-dose oral contraceptive (Microgynon) when receiving antibacterial treatment with a fluoroquinolone (ofloxacin). Adv Contracept 12(2):101-9 (1996 Jun).
- The American College of Obstetricians and Gynecologists (ACOG). Clinical management guidelines for Obstetrician-Gynecologists: the use of hormonal contraception in women with coexisting medical conditions. Am Coll Obstet Gynecol Pract Bull 18:6-7 (2000).
- Helms SE, Bredle DL, Zajic J, Jarjoura D, Brodell RT, Krishnarao I. Oral contraceptive failure rates and oral antibiotics. J Am Acad Dermatol 36(5 Pt 1):705-10 (1997 May).
- Kovacs GT, Riddoch G, Duncombe P, et al. Inadvertent pregnancies in oral contraceptive users. Med J Aust 150(10):549-51 (1989 May).