New Developments in Hormonal Therapy for Acne (FP Edition)

J. K. L. Tan, MD, FRCPC

Department of Medicine, University of Western Ontario, London, ON, Canada Windsor Clinical Research Inc, Windsor, ON, Canada

Background

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 increased 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.

• 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.

In Canada, 4 hormonal preparations are presently indicated for the treatment of acne.

• They all contain estrogen in the form of ethinyl estradiol (EE) and progestins, either with
  • minimal androgenicity
    • EE/ norgestimate
    • EE/ levonorgestrel
  • or antiandrogenic potential
    • EE/ drospirenone
    • EE/ cyproterone acetate.
• They all have demonstrated efficacy for the treatment of acne and have acceptable long-term safety profiles.
• A reasonable duration of use to determine effectiveness in clinical practice with these products is 6 months
• Typically, topical acne products would also be used in conjunction with OCs to accelerate onset of effect.
• In practice, improvement of acne at other sites, including the torso and shoulders, can also be expected.

EE 0.030mg/ Drospirenone 3mg

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

• This formulation is available in Canada and the US.
• Competitively binds to androgen receptors.
• Inhibits 5-reductase activity, which reduces sebum production.
• Reduces androgen biosynthesis.
• For antimineralocorticoid activity, the dose equivalence for DRSP 3mg is spironolactone 25mg.

EE/ Norgestimate

• EE 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’s global assessment scores.[Redmond GP, et al. Obstet Gynecol 89(4): 615-22 (1997 Apr).]

EE/ Levonorgestrel

• EE 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 (721 women treated for 6 cycles) showed:
    • Reduction in acne lesion counts:
      • 32%–47% inflammatory
      • 13%–25% noninflammatory
      • 23%–40% total lesions
    • Investigator’s global assessment scores were rated as clear to almost clear in 48%-58% of subjects.

EE/ Cyproterone Acetate

The combination of EE 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 acts as a potent antiandrogen:
• by competitive inhibition of testosterone and dihydrotestosterone (DHT) binding to the androgen receptor.
• by inhibiting gonadotropin secretion.
• Efficacious in mild-to-moderate facial acne based on smaller trials with variable study designs and parameters. [Tan J. J Cutan Med Surg 8(Suppl 4):11-5 (2004 Dec).]

Head to Head Studies

• Efficacy for treating acne vulgaris was evaluated in a randomized controlled trial with EE 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 were for 9 cycles
  • Median reduction in total facial acne lesions:
    • 62% for EE 0.030mg/ drospirenone 3mg
    • 59% for EE 0.035mg/ cyproterone acetate 2mg
  • Both formulations were effective for the treatment of acne and were well tolerated.
    • Adverse events were mild-to-moderate in intensity and typical of those associated with 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 women-years.
  • 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, 1.3) for venous thromboembolism
      • 0.3 vs. 0.3 (upper 95% CI, 1.2,1.5) for arterial thromboembolism.

Conclusion

The proven therapeutic benefits of OCs offer a valuable option 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.