New Developments in Hormonal Therapy for Acne

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

Introduction

Oral contraceptives (OCs) have been used for many years by dermatologists as a treatment option for women with acne. The onset of acne is triggered by the production of androgens. Oral contraceptives inhibit ovulation, thereby resulting in the prevention of androgen production. The lower serum androgen levels reduce sebum secretion, which consequentially exerts an antiacne effect. 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 (e.g., ethinyl estradiol/ cyproterone acetate)
• as one of two preferred forms of contraception for women treated with systemic isotretinoin.

These preparations have evolved to include less estrogen and incorporate progestins with less intrinsic androgenicity in order to reduce the potential risk of thromboembolic events, hepatic tumors, hypertension, altered glucose metabolism, and rare androgenic side-effects such as acne, hirsutism, and weight gain.

OCs for the Treatment of Acne

In Canada, four hormonal preparations are presently approved by Health Canada for the treatment of acne.

• All contain estrogen and progestins
• with minimal androgenicity
• ethinyl estradiol/ norgestimate
• ethinyl estradiol/ levonorgestrel
• with anti-androgenic potential
• ethinyl estradiol/ drospirenone
• ethinyl estradiol/ cyproterone acetate
• All have demonstrated efficacy in the treatment of acne and long-term safety profiles.

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Ethinyl Estradiol 0.030mg/ Drospirenone 3mg (Yasmin^®)

Drospirenone (DRSP) is a novel progestogen derived from spironolactone, which is an antiandrogen.

• DRSP 3mg combined with 0.030mg ethinyl estradiol
• Recently approved in Canada for the treatment of moderate acne.
• Competitively binds to androgen receptors.
• Inhibits 5á-reductase activity, which results in the down regulation of sebum production.
• Reduces androgen biosynthesis.
• For antimineralocorticoid activity, the dose equivalence for DRSP 3mg is spironolactone 25mg.
• Efficacy for treating acne vulgaris was evaluated in a randomized controlled trial with ethinyl estradiol 0.035mg/ cyproterone acetate 2mg as the active comparator.[van Vloten WA, et al. Cutis 69(4 Suppl):2-15 (2002 Apr).]
• 125 subjects aged 16-35 years with mild-to-moderate facial acne treated for 9 cycles
• Median reduction in total facial acne lesions:
• 62% for ethinyl estradiol 0.030mg/ drospirenone 3mg
• 59% for ethinyl estradiol 0.035mg/cyproterone acetate 2mg
• Both formulations were effective for treatment of acne and well tolerated
• Adverse events were mild-to-moderate in intensity and typical of those associated with OCs.

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

• Ethinyl estradiol 0.035mg with norgestimate in increasing doses, 0.180mg/ 0.215mg/ 0.250mg
• Norgestimate has low intrinsic androgenicity with low binding affinity for androgen receptors. It is strongly selective and avidly bound to progesterone receptor sites. This combination estrogen and progestin preparation produces a synergistic effect which enhances regulation of hormonal levels.
• Shown to be efficacious in moderate facial acne in two randomized placebo-controlled trials involving 324 subjects over 6 cycles.[Lucky AW, et al. J Am Acad Dermatol 37(5 Pt 1):746-54 (1997 Nov); Redmond GP, et al. Obstet Gynecol 89(4): 615-22 (1997 Apr).]
• Inflammatory lesions were reduced by 56%, noninflammatory lesions by 41%, and 32% achieved excellent improvement using investigator global assessment scores.[Redmond GP, et al. Obstet Gynecol 89(4): 615-22 (1997 Apr).]

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Ethinyl Estradiol/ Levonorgestrel (Alesse^®)

• Ethinyl estradiol 0.020mg and levonorgestrel 100ìg
• Shown to be efficacious for moderate facial acne in two randomized placebo-controlled trials.[Leyden J, et al. J Am Acad Dermatol 47(3):399-409 (2002 Sep); Thiboutot D, et al. Fertil Steril 76(3):461-8 (2001 Sep).]
• A compilation of both studies showed 721 women treated for 6 cycles.
• Significant improvements seen:
• Reduction in acne counts:
• 32%–47% inflammatory
• 13%–25% noninflammatory
• 23%–40% total lesions.
• Investigator global assessment scores were rated as clear to almost clear in 48%-58% of subjects.

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

The combination of ethinyl estradiol 0.035mg and cyproterone acetate 2mg 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 also acts as a potent antiandrogen:
• by inhibiting gonadotropin secretion.
• by competitive inhibition of testosterone and dihydrotestosterone (DHT) binding to the androgen receptor.

Efficacious in mild-to-moderate facial acne based on smaller trials with variable study designs and parameters, which produced data that could not be combined for metanalysis.[Tan J. J Cutan Med Surg 8(Suppl 4):11-5 (2004 Dec).]

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European Study Comparing Efficacy and Safety of OCs

• A European multinational, prospective, observational new-user cohort study evaluated the safety of DRSP-containing OCs and other OCs. [Dinger JC, et al. Contraception 75(5):344-54 (2007 May).]
• 58,674 women were observed for 142,475 womenyears.
• Serious adverse and fatal events were rare.
• Regression analysis of adverse cardiovascular events:
• Hazard ratios for DRSP-containing OCs vs. levonorgestrel-containing and other OCs
• 1.0 vs. 0.8 (upper 95% confidence intervals [CI], 1.8 and 1.3) for venous thromboembolism
• 0.3 vs. 0.3 (upper 95% CI, 1.2 and 1.5) for arterial thromboembolism.

The risks of adverse cardiovascular and other serious events in users of DRSP-containing OCs in this study were found to be similar to those associated with other OCs.

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Conclusion

The proven therapeutic benefits of OCs extend a valuable alternative to physicians for the treatment of acne. The accumulating evidence on the efficacy and safety of recently available drospirenone-containing hormonal preparations provides dermatologists with a new option for the treatment of acne and other hyperandrogenic disorders.

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