Acne vulgaris is the most common disorder seen by dermatologists in clinical practice. It affects approximately 80% of adolescents and young adults and persists into adulthood, especially in women. The multifactorial pathogenesis of acne often requires treatment with a combination of topical retinoids, benzoyl peroxide, and antibiotics.
These dosing regimens target 3 of the 4 factors in acne pathogenesis.
(1) follicular keratin plugs and microcomedema formation
(2) Bacteria
(3) Inflammation
The 4th factor that promotes the formation of acne is excessive sebum production. There is limited treatment in stopping sebum production and excretion. Isotretinoin, spironolactone, and compounded oral contraceptives have all been shown to reduce sebum. Spironolactone is widely prescribed by dermatologists but is not FDA approved for the treatment of acne. Many dermatologists now prescribe combination oral contraceptives, three of which are FDA-approved for the treatment of acne. Some dermatologists are still reluctant to prescribe these medications, even as a treatment option for acne. The following will review the mechanism of action of combination oral contraceptives for acne as well as their potential risks and benefits. In addition, potential “roadblocks” are compiled, including whether a pelvic exam and/or Pap smear is necessary to increase the safety of prescribing combination oral contraceptives.
Mechanism of action of combination oral contraceptives in the treatment of acne vulgaris
Androgens promote massive acne formation due to blockage of sebaceous glands. Androgens bind to androgen receptors located in the sebaceous glands, increasing the production and release of sebum. Androgen receptors are also present in hair follicles and when bound can promote the formation of microcomedones. If androgen activity can promote the development of acne vulgaris, then androgen blockade will improve acne.
There are 4 ways to block the role of androgens in acne in its entirety.
(1) reducing the amount of androgens produced by the gonads.
(2) blocking androgen receptors.
(3) reducing free, unbound and bioavailable testosterone by increasing sex hormone binding globulin (SHBG)
(4) inhibition of 5α-reductase activity to inhibit the conversion of weaker androgens to stronger androgens.
Combination oral contraceptives are a mixture of ethinyl estradiol (EE) and progesterone. the doses of EE and progesterone are different in each pill. Although some progesterone has androgen-like effects, when combined with EE, the net result produced is all anti-androgen. In particular, compounded oral contraceptives result in a decrease in gonadotropins, luteinizing hormone (LH) and follicle growth hormone (FSH). This blocks ovulation and blocks LH-induced production of ovarian androgens.EE also increases hepatic synthesis of SHBG, which binds free testosterone so that it cannot be converted to dihydrotestosterone or bind to androgen receptors. Some progesterone factors also inhibit 5α-reductase, which converts testosterone to the more active dihydrotestosterone. Drospirenone is the only progesterone approved by the US FDA for blocking androgen receptors and is a true anti-androgen drug, although not incorporated into EE.
Drospirenone is available in 2 packages in the United States.
1 containing 30 μg of EE and 3 mg of drospirenone (Yasmin®, Bayer, Montville, NJ).
The other contains 20 μg of EE and 3 mg of drospirenone (Yaz®, Bayer, Montville, NJ). The latter is FDA-approved for the treatment of moderate acne.
FDA-approved oral contraceptives for the treatment of moderate acne vulgaris
A number of combination oral contraceptives have been studied for the treatment of acne vulgaris. Three of them are FDA-approved for the treatment of moderate acne vulgaris: Ortho Tri-cyclen® (McNeil Janssen Pharmaceuticals, Raritan, NJ), Estrostep® (Warner-Chilcott, Rockaway, NJ), and Yaz® (Table 1).
(Table 1).
Ortho Tri-cyclen® contains 35 μg of EE and progressively increasing amounts of progesterone oxime norethindrone. approved by the FDA in 1997 for the treatment of moderate acne.
Estrostep® contains 20 μg of EE for the first 5 days, 30 μg for the next 7 days, and 35 μg for the last 9 days. the progesterone in Estrostep® is norethindrone acetate, which was approved by the FDA in 2001 for the treatment of acne.
Yaz® is a compounded oral contraceptive recently approved by the FDA for the treatment of moderate acne. It contains 20 μg of EE and 3 mg of drospirenone and is administered 24/4. It was approved in 2007 for the treatment of acne.
Risks of Combination Oral Contraceptives
Compounded oral contraceptives are associated with some potential risks. It increases the risk of venous thromboembolism (VTE) in women. This risk is age and dose-related. The World Health Organization (WHO) states that doses of combined oral contraceptives containing less than 50 μg of EE are not associated with the risk of VTE.
An increased risk of myocardial infarction (MI) has been reported with compounded oral contraceptives. As with many other potential risks of compounded oral contraceptives, the risk of myocardial infarction is age-related. Compounded oral contraceptives are contraindicated in women over the age of 35 who smoke.
Compounded oral contraceptives also increase the risk of ischemic and hemorrhagic strokes. It has also shown to be age- and dose-related.
The potential increased risk of breast cancer in users of combination oral contraceptives has been extensively studied.
Cervical cancer may also be associated with the use of combination oral contraceptives. The relative risk of cervical cancer for 4 years of combined oral contraceptive use is 1.33. The relative risk increases to 1.48 for 8 years of combined oral contraceptive use.
Benefits of the combination oral contraceptive pill
There are also many potential benefits for users of combination oral contraceptives. These include regulation of the menstrual cycle reducing concomitant blood loss and anemia, reduction in the formation of ovarian cysts and ectopic pregnancies. They also reduce fibrocystic breast changes, pelvic inflammatory disease, and endometrial and ovarian cancer.
Although they are prescribed for the treatment of acne, contraception is a definite benefit of these drugs.
Prescription Compounded Oral Contraceptives for Acne
Patient selection
Table 2 lists individuals who are not candidates for the use of combination oral contraceptives. Medication history and blood pressure measurements will help identify these individuals. Combination oral contraceptives are not recommended for women who are pregnant or within 6 months of giving birth. In addition, current breast cancer, women older than 35 years of age who smoke more than 15 cigarettes/day, and those with high blood pressure are contraindications to the use of combination oral contraceptives. Combination oral contraceptives are also contraindicated in patients with a current or previous history of deep vein thrombosis and/or pulmonary embolism, prolonged braking after major surgery, heart disease and stroke. Women of any age with migraine accompanied by neurological symptoms or over 35 years of age with any type of migraine are at increased risk with the use of compounded oral contraceptives. Finally, the use of combination oral contraceptives is contraindicated in patients with active hepatitis, severe cirrhosis, benign or malignant liver tumors. Contraindications to combination oral contraceptives containing drospirenone also include renal insufficiency, hyperaldosteronism, and hyperkalemia.
Patient education/counseling
It is important to inform patients about the appropriate use of combination oral contraceptives, to observe potential adverse effects and to establish appropriate expected outcomes. There are three options for how to initiate treatment with the combination oral contraceptive pill: (1) start the combination oral contraceptive pill on the first day of the next menstrual period, (2) start the combination oral contraceptive pill during or on the first Sunday after the next menstrual period, and (3) the combination oral contraceptive pill can be taken immediately after obtaining a negative pregnancy test. Option 1 is the most commonly used method and the one documented in the isotretinoin risk management procedure.
It is important to remind patients to take compounded oral contraceptives daily, although they are not used for contraception. Irregular use may result in unexpected bleeding as well as failure to achieve the desired outcome for acne treatment or contraception. Irregular bleeding or blood spots may occur within 3 months of the start of treatment is normal, but will disappear with continued treatment. If a pill is lost or forgotten, the patient needs to take a replacement for the forgotten pill as soon as possible. Sometimes 2 pills can be taken together if a full day is forgotten. Patients should also be reminded that combination oral contraceptives do not prevent sexually transmitted diseases. Other adverse reactions that have been reported include nausea, mood changes, and breast tenderness. Weight gain accompanying the combination oral contraceptive pill is moderate, if present. Adverse reactions other than blood spotting diminish with a decrease in EE.
Compounded oral contraceptives do not provide rapid improvement in acne. Patients need to be told that compounded oral contraceptives take at least 3 months to improve acne. During this 3 month period, combination therapy is important and can significantly reduce acne.
Physical examination: Previously, for many years, a pelvic examination was required prior to obtaining a prescription for a combination oral contraceptive. Now, long-term data on the use and safety of these drugs have softened these restrictions.
Potential drug interactions
Rifampicin and ashwagandha are the only anti-infective factors that interact with combination oral contraceptives. They enhance the metabolism of combination oral contraceptives via the cytochrome p450 (CYP)3A4 pathway. There is no evidence of an interaction between antibiotics commonly used to treat acne vulgaris and combination oral contraceptives. Some antiepileptic drugs, including carbamazepine and phenytoin sodium, also interact via the CYP
3A4 pathway and compounded oral contraceptives, increasing the failure rate of compounded oral contraceptives.
How I Prescribed Combination Oral Contraceptives to Treat Acne
Although combination oral contraceptives can be effective in treating acne and provide many benefits to patients, they are rarely used as monotherapy. In my experience, they are often combined with topical retinoids, topical benzoyl peroxide, and antibiotics. They are usually treated with compounded oral contraceptives only after acne has not improved well with conventional treatments. Any woman, with no known contraindications, can add a combination oral contraceptive. I use combination oral contraceptives in women who wish to use contraception or adjust their menstrual cycle.
In other women and adolescent girls, I use combination oral contraceptives when
(1) conventional treatments are not effective in controlling acne.
(2) Acne is cyclical and coincides with the menstrual cycle
(3) The patient complains of being too oily and/or is considering combination therapy with isotretinoin. Most of these patients do not have clinically significant androgen excess and do not require laboratory evaluation prior to initiation of a combination oral contraceptive. Women with significant androgen excess, including hirsutism and irregular menstruation, require laboratory evaluation prior to initiation of combination oral contraceptives. Baseline laboratory evaluations included free and total testosterone, dehydroepiandrosterone sulfate, LH, and follicle stimulating hormone.
Conclusion
The combination oral contraceptive pill is an important add-on treatment for acne in any woman with no known contraindications. Its full antiandrogenic effect is effective in improving acne and provides many other benefits to female patients. As with any other medication, there are potential adverse effects associated with the use of combination oral contraceptives. By learning the potential risks/benefits and selecting the appropriate patients, dermatologists need to become experts in prescribing these medications. When used appropriately, combination oral contraceptives can be effective, safe and easily tolerated medications for the treatment of acne vulgaris.
Do dermatologists need to prescribe hormonal contraceptives for acne? The answer is absolutely yes.