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Hormonal therapy for women with acne vulgaris

Hormonal therapy for women with acne vulgaris

Author
Jacqueline Junkins-Hopkins, MD
Section Editors
Robert P Dellavalle, MD, PhD, MSPH
Mark V Dahl, MD
Deputy Editor
Abena O Ofori, MD
Last literature review version 19.3: Fri Sep 30 00:00:00 GMT 2011 |This topic last updated: Sun Jun 12 00:00:00 GMT 2011 (More)

INTRODUCTION — Androgens play an important role in the pathogenesis of acne vulgaris. For some women with moderate to severe acne that does not respond to other therapies, hormonal therapies can be effective. The most common medications that are prescribed are oral contraceptives and spironolactone.

Options for hormonal therapy are discussed below. The role of androgens in acne and nonhormonal acne therapies are discussed elsewhere. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Treatment of acne vulgaris" and "Oral isotretinoin therapy for acne vulgaris" and "Light-based, adjunctive, and other therapies for acne vulgaris".)

ANDROGENS IN ACNE — Androgens stimulate the production of sebum by sebaceous glands and contribute to the accumulation of sebum and keratinous material in pilosebaceous follicles. As sebum and keratin amass within follicles, open or closed comedones are formed. Sebum also provides a growth medium for Propionibacterium acnes, a bacterium that resides in pilosebaceous follicles. Proliferation of P. acnes contributes to the inflammatory response seen in acne vulgaris. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Pathogenesis'.)

The normal rise in serum androgen levels that begins in the prepubertal period correlates with the start of increased sebum production in the skin. Increased sensitivity of sebaceous glands to circulating androgens may contribute to the development of acne [1] . Excessive levels of serum androgens also can increase risk for acne, and patients with disorders such as polycystic ovarian syndrome, congenital adrenal hyperplasia, adrenal tumors, or androgen-secreting ovarian tumors are more likely to develop this disorder. In one study of 52 women (age 18 to 35 years) with mild acne and their age-matched controls, polycystic ovary syndrome was significantly more common in the patients with acne than in the control group (27 versus 8 percent) [2] . Women who present with acne and concomitant hirsutism or menstrual irregularity should have a gynecologic and hormonal evaluation (picture 1). (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris", section on 'Hyperandrogenism'.)

OVERVIEW — Even in the absence of a hyperandrogenic state, hormonal therapies are useful for the treatment of acne in women. Hormonal therapy is typically used for post-menarchal adolescent and adult females with moderate to severe acne who are not trying to become pregnant. Women with milder acne who choose oral contraceptives for the purpose of pregnancy prevention can also experience the ancillary benefit of improvement in their acne. Hormonal therapy seems to be particularly useful in adult women who present with inflammatory acne involving the lower face and neck with premenstrual flares (picture 2) [3,4] .

Hormonal therapy is thought to improve acne through the inhibition of androgen action on pilosebaceous units. Estrogen in oral contraceptive agents suppresses ovarian androgen production and reduces the level of biologically available circulating androgens. Antiandrogenic agents such as spironolactone and drospirenone (a progestin in some oral contraceptive agents) competitively inhibit the binding of androgens to receptors on pilosebaceous unit [5] . (See "Overview of the use of estrogen-progestin contraceptives", section on 'Mechanisms of action'.)

When treating patients with moderate to severe acne, hormonal therapy should be used as part of a treatment regimen that contains a topical retinoid; concomitant therapy with topical or oral antimicrobial agent(s) may also be indicated (figure 1 and table 1) [6] . Aminimum of three to six months of therapy is required for evaluation of the efficacy of hormonal therapies.

Women with hyperandrogenism — Hormonal therapy is useful for the management of acne in women with hyperandrogenism [5,7] . Oral contraceptives, particularly those preparations with low androgenic progestins, are indicated for women with excessive ovarian androgen production (eg, polycystic ovarian syndrome). (See "Use of combination estrogen-progestin contraceptives in the treatment of hyperandrogenism and hirsutism".)

Glucocorticoids are indicated for women with excessive adrenal androgen production, such as in classical congenital adrenal hyperplasia. For those with nonclassical (late-onset) congenital adrenal hyperplasia, oral contraceptives rather than glucocorticoids are generally used. Both treatments suppress adrenal androgens, but oral contraceptives have fewer side effects and complications. (See "Diagnosis and treatment of nonclassic (late-onset) congenital adrenal hyperplasia due to 21-hydroxylase deficiency".)

ORAL CONTRACEPTIVES — Oral contraceptives are effective therapies for acne vulgaris in women. The estrogen component in oral contraceptives suppresses ovarian androgen production via the inhibition of gonadotropins, and increases sex hormone binding globulin, which results in reduced bioavailability of testosterone [8] . (See "Overview of the use of estrogen-progestin contraceptives", section on 'Mechanisms of action'.)

Efficacy — The first randomized trial documenting the efficacy of oral contraceptive therapy for acne vulgaris was a placebo-controlled trial that investigated the efficacy of a triphasic combination pill with norgestimate and ethinyl estradiol (Ortho Tri-Cyclen®) in women with moderate acne vulgaris (n = 250) [9] . The oral contraceptive group performed significantly better than placebo-treated patients for all primary efficacy measures, including inflammatory lesions (mean reduction 51 versus 35 percent), total lesions (mean reduction 46 versus 34 percent), and the investigator's global assessment (83 versus 63 percent). The significant placebo effect was likely due, in part, to improved skin care and more frequent visits for the study population overall. Since this trial, several other randomized trials evaluating the efficacy of other oral contraceptives in comparison to placebo have found results that favor the efficacy of oral contraceptives [10] .

Combination oral contraceptives with antiandrogenic progestins — Oral contraceptives with antiandrogenic progestins are a subclass of combination oral contraceptives. These include agents that contain cyproterone acetate, drospirenone, or dienogest plus an estrogen [11-13] . Oral contraceptives containing cyproterone acetate are not available in the United States, but are used in Europe [6] . Yasmin® (ethinyl estradiol 30 mcg/drospirenone 3 mg) and Yaz® (ethinyl estradiol 20 mcg/drospirenone 3 mg) are the two drospirenone-containing oral contraceptives that are prescribed in the United States.

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A pooled analysis of two placebo-controlled randomized trials with a total of 893 females with moderate facial acne found that patients treated with ethinyl estradiol 20 mcg/drospirenone 3 mg (Yaz®) for six cycles were more likely to attain clear or almost clear skin than patients treated with placebo (odds ratio [OR] 3.41, 95% CI 2.15-5.43) and had greater mean reductions in acne lesion counts [14] . In one trial, total lesion counts were reduced 46.3 percent for the combination oral contraceptive group and 30.6 percent for placebo group [15] . Beneficial effects were observed by the third cycle.

An oral contraceptive containing ethinyl estradiol 30 mcg/dienogest 2 mg was superior to placebo in another large randomized trial; total lesion counts were reduced by 55 versus 39 percent [13] . The only placebo-controlled study of oral cyproterone acetate is a small randomized trial (n = 40) in which a topical form of cyproterone acetate was compared to oral ethinyl estradiol 35 mcg/cyproterone acetate 2 mg and placebo [16] . The oral agent was superior to placebo for reduction of acne severity grade and lesion counts.

Choice of agent — All low-dose combination oral contraceptives are estrogen-dominant, which effectively makes all of these agents antiandrogenic [10,17-19] . Although the results of a few randomized trials have suggested slightly greater benefit of ethinyl estradiol 30 mcg/drospirenone 3 mg (Yasmin®) over ethinyl estradiol 35 mcg/norgestimate 0.180,0.125,0.250 mg (Ortho Tri-Cyclen®) [20] , and for cyproterone acetate containing oral contraceptives over levonorgestrel containing agents [21,22] , additional high-quality trials are necessary to confirm these results [10] . Similarly, while newer third generation progestins (norgestimate, desogestrel, and gestodene) are considered to be less androgenic than their second generation precursors (eg, levonorgestrel, norethindrone), data are inadequate to conclude that third generation agents offer superior efficacy for acne [10] .

Progestin-only contraceptives — Progestin-only contraceptives, including low dose oral pills and injections of medroxyprogesterone, may exacerbate acne [6] . The development or exacerbation of acne has been reported in connection with the levonorgestrel intrauterine device and etonogestrel implant [23] . Patients with acne may benefit from alternative contraceptive options. (See "Overview of contraception".)

Side effects — The risks and benefits of taking oral contraceptives should be considered and discussed with all patients prior to the initiation of therapy. Thromboembolism is a potential serious adverse effect of oral contraceptive use [24,25] , and treatment should be avoided in patients with underlying thrombophilic disorders or a history of a venous thromboembolic event. Additional guidelines for the use of oral contraceptives are provided in a table (table 2). (See "Risks and side effects associated with estrogen-progestin contraceptives" and "Overview of the use of estrogen-progestin contraceptives", section on 'Contraindications'.)

Drospirenone has a potassium-sparing diuretic effect similar to the drug spironolactone. An increased risk for hyperkalemia was not demonstrated in a cohort study of 22,429 patients given ethinyl estradiol 30 mcg/drospirenone 3 mg and 44,858 given other oral contraceptives [6] . However, based on theoretical concerns for hyperkalemia in selected patients, treatment with Yaz® and Yasmin® is contraindicated in patients with renal insufficiency, hepatic dysfunction, and adrenal insufficiency [26] . In addition, monitoring of serum potassium is recommended during the first cycle for patients taking medications with potassium-retaining properties [26] .

Oral contraceptives and antibiotics — In some cases, patients may be treated with oral contraceptives and oral antibiotics simultaneously. There is no definitive evidence that oral antibiotics, with the exception of rifampin, reduce oral contraceptive effectiveness for pregnancy prevention [27] . The use of antibiotics other than rifampin does not warrant an additional form of pregnancy protection. (See "Overview of the use of estrogen-progestin contraceptives", section on 'Antibiotics'.)

ANDROGEN RECEPTOR BLOCKERS — Androgen receptor blockers act at the peripheral receptor level to decrease sebum production. Androgen receptor blockers that have been used in the treatment of acne include spironolactone, cyproterone acetate, and flutamide. Cyproterone acetate is not available in the United States, but is prescribed as a sole agent or as a component of oral contraceptives elsewhere. Flutamide can cause fatal hepatitis, and is infrequently used for acne [28,29] .

Spironolactone — Spironolactone is an oral antiandrogen that blocks androgen receptors and inhibits androgen biosynthesis [30] . It has been used to treat disorders such as acne, hirsutism, and androgenic alopecia in women. Spironolactone therapy may be considered for women whose moderate to severe acne has not responded to conventional treatments and who prefer to avoid oral isotretinoin.

Efficacy and administration — Although the authors of a 2009 systematic review of randomized trials found insufficient evidence to confirm the efficacy of spironolactone for women with acne [31] , several studies (including two small randomized trials and case series) have reported treatment benefit [32-36] . Our clinical experiences also suggest that treatment is useful some patients.

Spironolactone has been prescribed in doses of up to 200 mg/day for acne [32-34,37] . However, lower doses may be effective and may reduce the risk for adverse effects [35,38,39] . A retrospective analysis found that responses to 50 to 100 mg/day were similar to previously reported responses to doses of 150 to 200 mg/day [38] . Additionally, in a series of 35 women with acne who were treated with 50 mg twice daily for 16 consecutive days per month for three months, 24 out of 28 women who completed treatment had clinically significant improvement [35] .

We typically utilize doses of 50 to 100 mg/day (given in two divided doses) when treating women with acne [40] . Initiating treatment with total doses of 25 to 50 mg/day, with subsequent dose escalation according to patient tolerance and response, will help to minimize side effects [6] . Additional studies are necessary to explore the role of spironolactone in women with acne [5,40] .

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Side effects — Side effects of spironolactone include menstrual irregularities, breast tenderness, minor gastrointestinal symptoms, orthostatic hypotension, and central nervous system symptoms (headaches, dizziness, and fatigue). Side effects (excluding central nervous system symptoms) are less frequent at lower doses (≤100 mg/day) [38] .

Spironolactone is a potassium-sparing diuretic, and hyperkalemia is a potentially serious adverse effect. This side effect is most likely to occur at high doses and in patients with renal insufficiency or severe heart failure [41,42] . The serum potassium and blood pressure should be monitored periodically in women who take spironolactone, particularly early in the course of therapy [30,41] .

The oral contraceptive progestin drospirenone (Yasmin®, Yaz®) also possesses potassium-sparing diuretic properties; 3 mg of drospirenone is equivalent to approximately 25 mg of spironolactone [43] . Although hyperkalemia was not demonstrated in one small prospective study of patients concurrently taking oral contraceptives with drospirenone and 100 mg/day of spironolactone [44] , patients treated with these agents simultaneously should be monitored for hyperkalemia. Potassium levels at baseline and four to six weeks after starting therapy have been suggested [30] .

The development of tumors, including mammary tumors, in rats treated with spironolactone or a related compound has been reported [45] . The relationship between spironolactone use and breast cancer has been debated [46-49] . However, no definitive evidence linking human breast or other estrogen-dependent tumors to the use of spironolactone exists. It is unclear whether there is increased risk for women with a personal or family history of breast or other estrogen-dependent malignancies [41,48] .

Feminization of the male fetus occurs in patients who become pregnant while taking spironolactone. The co-administration of spironolactone with an oral contraceptive is advised because of this serious fetal effect, along with the menstrual irregularities that may occur during treatment [30] .

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

  • Basics topics (see "Patient information: Acne (The Basics)")
  • Beyond the Basics topics (see "Patient information: Acne")

SUMMARY AND RECOMMENDATIONS

  • Androgens play a key role in the development of acne vulgaris through the induction of sebum production. Thus, antiandrogenic therapies can be useful for the management of female patients with moderate to severe acne. (See 'Androgens in acne' above.)
  • Androgen levels are normal in the majority of women with acne. Women with signs of hyperandrogenism should be evaluated for underlying disorders such as polycystic ovarian syndrome, congenital adrenal hyperplasia, or adrenal or ovarian tumors. Women without hyperandrogenism whose acne has been unresponsive to other therapies can benefit from treatment with hormonal therapies. (See 'Overview' above.)
  • Hormonal therapy should be prescribed as part of an acne treatment regimen containing topical retinoids with or without antimicrobial agents. Oral contraceptives and spironolactone are the most common hormonal agents utilized for the treatment of acne. A minimum of three to six months of therapy is required in order to evaluate treatment efficacy. (See 'Overview' above.)
  • In women with moderate to severe acne who have had an inadequate response to topical therapy and oral antibiotics and who do not desire pregnancy, we suggest the use of combination oral contraceptives (Grade 2A). Women with milder acne who choose oral contraceptives for pregnancy prevention can experience the collateral benefit of improvement in their acne. Although newer third generation progestins have lower androgenicity, all low-dose combination oral contraceptives can be used for the treatment of acne. (See 'Oral contraceptives' above.)
  • Contraceptives containing progestins only can exacerbate acne and cannot be used for treatment of this condition. (See 'Progestin-only contraceptives' above.)
  • Spironolactone is the most common androgen receptor blocker used for the treatment of acne in the United States. In adult women with moderate to severe acne that is unresponsive to topical treatment, oral antibiotics, and oral contraceptives, we suggest treatment with spironolactone (Grade 2B). Topical retinoids should be continued; in women who have had no response to antimicrobials, they can be discontinued. A reasonable alternative to spironolactone would be to proceed to therapy with oral isotretinoin. (See 'Spironolactone' above.)
  • Spironolactone can cause fetal harm and menstrual irregularity, and is usually given with an oral contraceptive. Patients should be monitored for hyperkalemia. (See 'Spironolactone' above.)

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