Hormonal Agents Approved for Treatment of Acne

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

What is Acne?

Acne is an occlusional and inflammatory disorder of pilosebaceous follicles (oil pores) resulting from the combined effects of:

• androgenic hormones (testosterone, dihydrotestosterone, hydroxyprogesterone)
• follicular bacteria (Propionobacterium acnes),
• abnormal desquamation of the pore orifice,
• excessive sebum excretion.

Hormonal therapy

Hormonal agents have long been recognized as being effective for treating acne in women. This paper focuses on agents officially indicated for treatment of acne in Canada:

• Ethinyl estradiol 0.020mg and levonorgestrel 0.100mg (Alesse®)
• Ethinyl estradiol 0.035mg and cyproterone acetate 2mg (Diane-35®)
• Ethinyl estradiol 0.035mg and norgestimate in increasing doses (0.180mg, 0.215mg and 0.250mg each for 7 days (Ortho Tri-Cyclen®).

These agents may be used in women with:

• moderate acne as adjunctive therapy to topicals in women desiring contraception.
• severe acne in women unresponsive to topical agents and oral antibiotics (Diane®-35).
• severe acne requiring oral isotretinoin as one of two preferred forms of contraception.

Spironolactone is a synthetic steroid antiandrogen that competitively binds androgen receptors, inhibits 5-alpha-reductase activity, and reduces androgen biosynthesis. It has been used for treatment of acne in doses ranging from 50- 200mg/day. Due to the limited number of trials and small sample sizes, the efficacy of spironolactone for treatment of acne has been deemed indeterminate by a recent Cochrane review.[Farquhar C, et al. The Cochrane Library (Oxford) 2; CD000194 (2003).]

Treatment Duration

While improvement in acne is generally noted by the second cycle with these agents, longer treatment durations of 6 cycles or more provide for greater effectiveness.

Consider long-term maintenance treatment while acne is active to avoid the potential for rebound of symptoms on discontinuation. A statement issued by the Society of Obstetricians and Gynaecologists of Canada (SOGC) stated that “Repeated 'stop-start' regimens are not an optimal strategy for treating androgen-dependent disorders.”

Summary of Evidence

Comparing Hormonal Treatments

While there are no controlled clinical trials on the relative efficacy of these 3 agents in treating acne, a survey of Canadian acne patients previously treated with these agents indicated that

• Ethinyl estradiol 0.035mg and cyproterone acetate 2mg (Diane®-35) was ranked to be the most effective of the 3 agents.
• Effectiveness ratings of moderate-extremely were highest for Diane®-35 (42%) compared to Ethinyl estradiol 0.035mg and norgestimate in increasing doses (0.180mg, 0.215mg and 0.250mg each for 7 days Ortho Tri-Cyclen® (22%) and Ethinyl estradiol 0.020mg and levonorgestrel 0.100mg (Alesse®) (19%).
• The 3 treatments have different mechanisms of action because Diane®-35 has progesterone with antiandrogenic properties in addition to the estrogen components.

[Tan J. Effectiveness of Hormonal Treatment in Acne – The Canadian Acne Epidemiological Survey. Presented at: Dermatology Update 2005, Montreal, Canada.]

Safety

The use of these agents may be associated with minor adverse events such as nausea, breast tenderness, headaches, mood changes, and weight gain. Serious potential complications include venous thromboembolism (VTE), myocardial infarction, and stroke. While the risk of low-dose combined hormonal treatments for venous thromboembolism (VTE) is increased 3-4 fold, the magnitude of this risk is of minimal clinical significance in women without additional risk factors [Contraception Guidelines Committee of SOGC. Canadian Clinical Practice Guidelines: Combined Hormonal Contraception. J Obstet Gynaecol Can 26(3):219-54 (2004).] A recent comprehensive epidemiological review did not demonstrate an increase in VTE risk for Diane®-35 [Spitzer WO. J Obstet Gynaecol Can 25:1011-8 (2003)]. Hypertension and smoking are independent risk factors for myocardial infarction and stroke in patients taking oral contraceptive pills. Accordingly, conditions contraindicating the use of hormonal treatments include VTE, cerebrovascular or coronary artery disease, headaches with focal neurologic symptoms, diabetes with complications, cigarette smoking >35 years, hypertension >160/100mmHg or with concomitant vascular disease, and conditions associated with prolonged immobilization.

Conclusion

Hormonal agents are important, effective therapeutic options for women across the spectrum of acne severity. The three preparations approved in Canada for this indication have safety profiles similar to conventional oral contraceptives.

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