Treating Acne Vulgaris: Systemic, Local and Combination Therapy

Laura J Savage; Alison M Layton

Disclosures

Expert Rev Clin Pharmacol. 2010;13(4):563-580. 

In This Article

Hormonal Therapies

Hormonal influences have an important role in the pathogenesis of acne. Increased sebum production owing to androgens acting at the sebaceous follicle is a prerequisite for acne in all patients.[91–93] Prior to puberty, the adrenal glands produce increasing amounts of dehydroepiandrosterone sulfate (DHEAS), which can be metabolized into more potent androgens in the skin, driving enlargement of the sebaceous gland and increased sebum production.[93] Both males and females have acne that is related to increased sensitivity of the sebaceous gland to androgens.[94] In women, aberrant excess production of androgens from the ovary may also cause acne, and should be excluded in females with acne that is persistent, of late onset or associated with hirsutism.[94] Serological investigation in these women has revealed high circulating levels of free testosterone and DHEAS and a low concentration of sex hormone-binding globulin.[95,96]

However, it is important to note that hormone therapy can be very effective in females with acne whether their serum androgens are normal or abnormal.[97] Although females with acne may have higher levels of serum androgens compared with women without acne, these levels are mostly within the normal range. Hormone therapies are most effective in adult females with persistent facial inflammatory papules and nodules. Often, such women report an association between the lead up to their menstrual period and a flare of their acne, consisting of a few tender, deep-seated inflammatory lesions.[13] Such patients have often experienced a frustrating period of minimal clinical improvement with other therapies, in particular, multiple courses of topical and oral antibiotics.

Hormone manipulation is therefore an additional resource in the therapeutic armamentarium for female patients with acne. Hormonal investigations and treatments are indicated when acne is recalcitrant and standard treatments have failed, as well as when oral isotretinoin is inappropriate, not available or when rapid relapse has occurred after repeated courses.[15] They are also desirable when menstrual control and/or contraception are required alongside acne therapy.

All available treatments share the common goal of opposing the effects of androgens on the sebaceous gland, and, to a lesser extent, the follicular keratinocyte.[13] This can be accomplished with the use of estrogens, androgen receptor blockers (cyproterone acetate [CPA], chlormadinone acetate, spironalactone, drospirenone, desogestrel and flutamide) or agents designed to inhibit the endogenous production of androgens by the ovary (e.g., oral contraceptives, CPA and gonadotrophin releasing agonists) or adrenal gland (e.g., low-dose glucocorticoids).

Inhibitors of Adrenal Androgen Production

Glucocorticoids in low doses can suppress the adrenal production of androgens. They are indicated for patients, both male and female, who have an elevated DHEAS level associated with late-onset congenital adrenal hyperplasia, caused by an inherent deficiency of 11-hydroxylase or 21-hydroxylase enzymes. Deficiency of 21-hydroxylase is present in approximately 3% of hirsute women and mutations in the gene encoding this enzyme are found more frequently in women with acne than in those without. Low-dose prednisolone (2.5–5 mg) or dexamethasone (0.25–0.75 mg) given at night (or alternative nights) can be sufficient to suppress adrenal androgen production and subsequently reduce sebum production by up to 50% with a concomitant improvement in acne.[92,98,99] Periodic assessment of DHEAS should be performed to monitor the effect of glucocorticoids on androgen production. Adrenal suppression is a potential adverse effect, and is observed more commonly with dexamethasone.[1] It is therefore recommended that adrenocorticotropic hormone stimulation tests are performed 2–3 months after the initiation of therapy.[13]

Several studies have shown that glucocorticoids given alongside cyclical estrogen can successfully moderate sebum production in recalcitrant acne, acheiving a greater reduction in plasma androgen levels than with either agent alone.[92,100,101] However, the doses of estrogen used in these studies were much higher than the dose in most oral contraceptives (80–100 µg), which in practice would need to be balanced against the greater potential for adverse effects such as venous thromboembolism (VTE).

Inhibitors of Ovarian Androgen Production

Oral contraceptives are the main treatment modality used to reduce androgen production from the ovaries. A Cochrane systematic review of the effectiveness of combined oral contraceptives (COCs) for the treatment of facial acne confirmed that COCs reduced lesion counts, severity grades and self-assessment scores compared with placebo.[102] Oral contraceptives recommended for the treatment of acne are usually a combined preparation containing estrogen (most commonly ethinyl estradiol) and a progestin with anti-androgenic activity.

Estrogens are particularly valuable in women with clinical evidence of hyperandrogenism. All COCs, provided that estrogen is given at a sufficient dose, will decrease sebum production and have the potential to improve acne.[13,15] Their actions are twofold; estrogen increases the hepatic production sex hormone-binding globulin, which binds and thus reduces levels of free circulating testosterone. In addition, estrogens suppress the ovarian production of androgens by suppressing gonadotrophin release from the pituitary, resulting in lower serum androgen levels and less seborrhea. However, the dose of estrogen required to suppress sebum production is often greater than the dose required to suppress ovulation. The dose of estrogen in conventional oral contraceptives has been reduced in recent years, with many third-generation preparations containing just 20 µg of ethinyl estradiol, which on its own is insufficient to control seborrhea in most female patients with acne.[15]

The efficacy of estrogen in managing seborrhea can be enhanced through the addition of a progestin with anti-androgenic activity. The progestins traditionally included in COCs include estranes and gonanes, which are derived from 19-nortestosterone and CPA. Third-generation agents contain newer progestins including gestodene, desogestrel and norgestimate, which collectively are less selective for the androgen and more selective for the progesterone receptor, making them less effective in acne.[103] This is supported by limited study data that confirms that CPA-containing COCs achieve better efficacy than preparations containing desogestrel or levonorgestrel.[102] Drosperinone, found in Yasmin® (Bayer PLC, Berkshire, UK), is a novel progestin derived from 17a-spironalactone, and thus has both antimineralocorticoid and anti-androgenic activity, and has also proved successful in the treatment of acne.[104]

Gonadotrophin-releasing Agonists

Gonadotrophin-releasing agonists, such as nafarelin, leuprolide and buserelin, have demonstrated efficacy in the treatment of acne and hirsutism in females both with and without endocrine abnormalities.[105] Administered as either a nasal spray or injection, gonadotrophin releasing agonists inhibit ovarian androgen production by interrupting the cyclical release of luteinizing hormone and follicle-stimulating hormone from the pituitary. However, their use is limited somewhat by the potential for adverse effects including reduced bone mass, headache and menopausal symptoms, caused by the suppression of ovarian estrogen production.

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