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
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.
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.
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|
|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*|
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.
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.
- 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).
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- 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).
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