New Developments in Hormonal Therapy for Acne

J. K. L. Tan, MD, FRCPC
Department of Medicine, University of Western Ontario, London, ON, Canada Windsor Clinical Research Inc, Windsor, ON, Canada

ABSTRACT

Oral contraceptives (OCs) are a valuable option for the treatment of women with acne. The use of OCs can be considered across the spectrum of acne disease severity in women. In Canada, three preparations are approved for mild-to-moderate acne, and a fourth is indicated for severe acne. These formulations contain estrogen in the form of ethinyl estradiol and a progestin. In Canada, the most recently approved OC is ethinyl estradiol 0.03mg and drospirenone 3mg (Yasmin^®, Bayer). With the accumulating evidence on the efficacy and safety of drospirenone-containing hormonal preparations, this formulation provides dermatologists with a new treatment option for acne and other hyperandrogenic disorders.

Key Words: Acne vulgaris, oral contraceptives, ethinyl estradiol, cyproterone acetate, drospirenone, norgestimate, levonorgestrel

For many years, oral contraceptives (OCs) have been used by dermatologists as a treatment option for women with acne. OCs that are indicated for use in acne are effective across the spectrum of disease severity:

• in mild acne as an adjunct to topical therapy for female patients desiring contraception
• in moderate acne as a form of systemic therapy
• in severe acne
• as a primary form of therapy
• as one of two preferred forms of contraception in women treated with systemic isotretinoin.

From their inception, these preparations have evolved to include less estrogen and incorporate progestins with less intrinsic androgenicity. These modifications were undertaken to reduce the potential risk of thromboembolic events, hepatic tumors, hypertension, altered glucose metabolism, and androgenic side-effects.

OCs for the Treatment of Acne

In Canada, four hormonal preparations are presently indicated for the treatment of acne. These preparations all contain estrogen and progestins with either minimal androgenicity (i.e., ethinyl estradiol/ norgestimate, and ethinyl estradiol/ levonorgestrel ) or antiandrogenic potential (i.e., ethinyl estradiol/ cyproterone acetate, and most recently, ethinyl estradiol/ drospirenone). Their demonstrated efficacy and long-term safety profile advocate their use in various grades of acne in women. Evidence supporting the use of these agents in acne was recently reviewed in the Journal of Cutaneous Medicine and Surgery,¹ and is summarized briefly here.

Ethinyl Estradiol/ Norgestimate (Ortho Tri-Cyclen^®)

Ethinyl estradiol 0.035mg with norgestimate in increasing doses, 0.180mg/ 0.215mg/ 0.250mg (Ortho Tri-Cyclen^®, Ortho-McNeil), was shown to be efficacious in moderate facial acne in two randomized placebo-controlled trials involving 324 subjects who were treated for 6 cycles.2,3 Significant improvements in lesion counts and investigator global assessment scores were observed. Inflammatory lesions were reduced by 56%, noninflammatory lesions by 41%, and 32% achieved excellent improvement. Norgestimate has low intrinsic androgenicity with low binding affinity for androgen receptors, whereas it is strongly selective and avidly bound to progesterone receptor sites.

Ethinyl Estradiol/ Levonorgestrel (Alesse^®)

Ethinyl estradiol 0.020mg and levonorgestrel 100ìg (Alesse^®, Wyeth Canada) was shown to be efficacious in moderate facial acne in two randomized placebo-controlled trials involving 721 women who were treated for 6 cycles.^4,5 Significant improvements were noted in lesion count, with reduction in acne counts of: 32%–47% inflammatory, 13%–25% noninflammatory, and 23%–40% total lesions. Investigator global assessment scores were rated as clear to almost clear in 48%-58% of subjects.

Ethinyl Estradiol/ Cyproterone Acetate (Diane-35^®)

The combination of ethinyl estradiol 0.035mg and cyproterone acetate 2mg (Diane-35^®, Bayer Healthcare) has been available as a hormonal treatment for acne in Canada since 1998. Cyproterone acetate is an analogue of hydroxyprogesterone and has progestational activity. It acts as a potent antiandrogen by competitive inhibition of testosterone and DHT binding to the androgen receptor and by inhibiting gonadotropin secretion. The best current evidence for the efficacy of this OC is in the treatment of mild-to-moderate facial acne, and is derived from trials with relatively small sample sizes, variable efficacy outcomes, varying trial durations, and the absence of placebo-controls.¹

Drospirenone

Spironolactone, a synthetic steroid, is an antiandrogen that competitively binds to androgen receptors, inhibits 5á-reductase activity, and reduces androgen biosynthesis. This agent, in doses of 50-200mg/day, has been shown to be efficacious for acne, although the trials have been small, and differed in dosages evaluated, outcome parameters, and reporting methodology.1 Drospirenone (DRSP) is a novel progestogen derived from spironolactone and has both antiandrogenic and antimineralocorticoid activity. DRSP 3mg has been combined with two different doses of ethinyl estradiol: 0.030mg for Yasmin^®, Bayer HealthCare; and 0.020mg for YAZ^®, Bayer Schering Pharma AG. Yasmin^® was recently approved for the treatment of acne in Canada, while both formulations are available in the US. For antimineralocorticoid activity, the dose equivalence for DRSP 3mg is spironolactone 25mg.⁶

Ethinyl Estradiol/ Drospirenone (Yasmin^®)

The efficacy of Yasmin^® for treating acne vulgaris was evaluated in a randomized controlled trial with Diane-35^® as the active comparator. One hundred and twenty-five subjects aged 16-35 years with mild-to-moderate facial acne were recruited for a 9-cycle duration trial. Median reduction in total facial acne lesions was 62% for Yasmin^® and 59% for Diane-35^® after 9 cycles. Thus, Yasmin^® was found to be as efficacious as Diane-35^® in the treatment of acne. Both preparations were well-tolerated, with adverse events being mild-to-moderate in intensity and typical of those associated with OCs.⁷

The safety of OCs containing ethinyl estradiol 0.030mg and DRSP 3mg was compared with other OCs in a European multinational, prospective, observational, new-user cohort study.8 A total of 58,674 women were observed for 142,475 women-years. Serious adverse and fatal events were rare. Regression analysis of adverse cardiovascular events yielded hazard ratios for DRSP-containing OCs vs. levonorgestrel-containing and other OCs of 1.0 and 0.8 (upper 95% confidence limits, 1.8 and 1.3) for venous, and 0.3 and 0.3 (upper 95% confidence limits, 1.2 and 1.5) for arterial thromboembolism, respectively. Thus, the risks of adverse cardiovascular and other serious events in users of DRSP-containing OCs were found to be similar to those associated with other OCs.

Yasmin^® has also been studied in other conditions associated with hyperandrogenism. Woman with polycystic ovary syndrome (PCOS) have elevated androgen levels that can cause acne, hirsutism, alopecia, weight gain, irregular menstruation and infertility. In an open-label study of PCOS, 20 women with this condition were evaluated over six cycles.9 At the end of the study, significant improvement was observed in lowered serum testosterone levels and increased sex hormone-binding globulin levels. In another study of women with PCOS, levels of androstenedione, dehydroepiandrosterone sulfate, testosterone, and free testosterone were reduced when treated with Yasmin^®.¹⁰

Ethinyl Estradiol/ Drospirenone (YAZ^®)

YAZ^® combines ethinyl estradiol 0.020mg and drospirenone 3mg in a 24/4 active/inert oral contraceptive regimen. In the US, this OC is indicated for premenstrual dysphoric disorder. In January 2007, US FDA approval was obtained for moderate acne that was based on the results of two multicenter, double-blind, randomized, placebo-controlled studies.11 These trials involved a total of 889 subjects with moderate acne, ranging from 14-45 years of age, who were randomized to receive YAZ^® or placebo for six 28-day cycles. A rating of clear/ almost clear on the Investigator Global Assessment was observed in 18% of YAZ^®-treated subjects compared with 6% on placebo. Mean reduction in inflammatory lesion counts was 15 (49%) in YAZ^®-treated subjects compared with 11 (33%) on placebo. Total lesion and non-inflammatory count changes were similar in both groups.

Conclusion

The accumulating evidence on the efficacy and safety of DRSP-containing hormonal preparations for these indications provides dermatologists with a new option for the treatment of acne and other hyperandrogenic disorders.

References

1. Tan J. Hormonal treatment of acne: review of current best evidence. J Cutan Med Surg 8(Suppl 4):11-5 (2004 Dec).
2. 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).
3. 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).
4. Leyden J, Shalita A, Hordinsky M, Swinyer L, Stanczyk FZ, Weber ME. Efficacy of a low-dose oral contraceptive containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel for the treatment of moderate acne: A randomized, placebo-controlled trial. J Am Acad Dermatol 47(3):399-409 (2002 Sep).
5. Thiboutot D, Archer DF, Lemay A, Washenik K, Roberts J, Harrison DD. A randomized, controlled trial of a low-dose contraceptive containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel for acne treatment. Fertil Steril 76(3):461-8 (2001 Sep).
6. Drospirenone + ethinyl estradiol (Yasmin^®) product monograph, http://berlex.bayerhealthcare.com/html/products/pi/fhc/Yasmin_PI.pdf, accessed July 31, 2007.
7. van Vloten WA, van Haselen CW, van Zuuren EJ, Gerlinger C, Heithecker R. The effect of 2 combined oral contraceptives containing either drospirenone or cyproterone acetate on acne and seborrhoea. Cutis 69(4 Suppl):2-15 (2002 Apr).
8. Dinger JC, Heinemann LA, Kühl-Habich D. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 75(5):344-54 (2007 May).
9. Pehlivanov B, Mitkov M. Efficacy of an oral contraceptive containing drospirenone in the treatment of women with polycystic ovary syndrome. Eur J Contracept Reprod Health Care 12(1):30-5 (2007 Mar).
10. De Leo V, Morgante G, Piomboni P, Musacchio MC, Petraglia F, Cianci A. Evaluation of effects of an oral contraceptive containing ethinyl estradiol combined with drospirenone on adrenal steroidogenesis in hyperandrogenic women with polycystic ovary syndrome. Fertil Steril 88(1):113-7 (2007 Jul).
11. Drospirenone + ethinyl estradiol (Yaz^®) product monograph, http://berlex.bayerhealthcare.com/html/products/pi/fhc/YAZ_PI.pdf, accessed July 27, 2007.

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