of acne and facial flushing and can cause significant skin irritation. generally speaking, retinoids increase the skin's sensitivity to sunlight and are therefore recommended for use at night. tretinoin is the least expensive of the topical retinoids and is the most irritating to the skin, whereas adapalene is the least irritating but costs significantly more. most formulations of tretinoin are incompatible for use with benzoyl peroxide. tazarotene is the most effective and expensive topical retinoid but is usually not as well tolerated. in 2019 a tazarotene lotion formulation, marketed to be a less irritating option, was approved by the fda. retinol is a form of vitamin a that has similar but milder effects and is present in many over-the-counter moisturizers and other topical products. isotretinoin is an oral retinoid that is very effective for severe nodular acne, and moderate acne that is stubborn to other treatments. one to two months of use is typically adequate to see improvement. acne often resolves completely or is much milder after a 4–6 month course of oral isotretinoin. after a single round of treatment, about 80% of people report an improvement, with more than 50% reporting complete remission. about 20% of people require a second course, but 80% of those report improvement, resulting in a cumulative 96% efficacy rate. there are concerns that isotretinoin is linked to adverse effects, like depression, suicidality, and anemia. there is no clear evidence to support some of these claims. isotretinoin has been found in some studies to be superior to antibiotics or placebo in reducing acne lesions. however, a 2018 review comparing inflammatory lesions after treatment with antibiotics or isotretinoin found no difference. the frequency of adverse events was about twice as high with isotretinoin use, although these were mostly dryness-related events. no increased risk of suicide or depression was conclusively found. medical authorities strictly regulate isotretinoin use in women of childbearing age due to its known harmful effects in pregnancy. for such a woman to be considered a candidate for isotretinoin, she must have a confirmed negative pregnancy test and use an effective form of birth control. in 2008, the united states started the ipledge program to prevent isotretinoin use during pregnancy. ipledge requires the woman to have two negative pregnancy tests and to use two types of birth control for at least one month before isotretinoin therapy begins and one month afterward. the effectiveness of the ipledge program is controversial due to continued instances of contraception nonadherence. antibiotics people may apply antibiotics to the skin or take them orally to treat acne. they work by killing c. acnes and reducing inflammation. although multiple guidelines call for healthcare providers to reduce the rates of prescribed oral antibiotics, many providers do not follow this guidance. oral antibiotics remain the most commonly prescribed systemic therapy for acne. widespread broad-spectrum antibiotic overuse for acne has led to higher rates of antibiotic-resistant c. acnes strains worldwide, especially to the commonly used tetracycline (e.g., doxycycline) and macrolide antibiotics (e.g., topical erythromycin). therefore, dermatologists prefer antibiotics as part of combination therapy and not for use alone. commonly used antibiotics, either applied to the skin or taken orally, include clindamycin, erythromycin, metronidazole, sulfacetamide, and tetracyclines (e.g., doxycycline or minocycline). doxycycline 40 milligrams daily (low-dose) appears to have similar efficacy to 100 milligrams daily and has fewer gastrointestinal side effects. however, low-dose doxycycline is not fda-approved for the treatment of acne. antibiotics applied to the skin are typically used for mild to moderately severe acne. oral antibiotics are generally more effective than topical antibiotics and produce faster resolution of inflammatory acne lesions than topical applications. the global alliance to improve outcomes in acne recommends that topical and oral antibiotics are not used together. oral antibiotics are recommended for no longer than three months as antibiotic courses exceeding this duration are associated with the development of antibiotic resistance and show no clear benefit over shorter durations. if long-term oral antibiotics beyond three months are used, then it is recommended that benzoyl peroxide or a retinoid be used at the same time to limit the risk of c. acnes developing antibiotic resistance. the antibiotic dapsone is effective against inflammatory acne when applied to the skin. it is generally not a first-line choice due to its higher cost and a lack of clear superiority over other antibiotics. topical dapsone is sometimes a preferred therapy in women or for people with sensitive or darker-toned skin. it is not recommended for use with benzoyl peroxide due to the risk of causing yellow-orange skin discoloration with this combination. minocycline is an effective acne treatment, but it is not a first-line antibiotic due to a lack of evidence that it is better than other treatments, and concerns about its safety compared to other tetracyclines. sarecycline is the most recent oral antibiotic developed specifically for the treatment of acne, and is fda-approved for the treatment of moderate to severe inflammatory acne in patients nine years of age and older. it is a narrow-spectrum tetracycline antibiotic that exhibits the necessary antibacterial activity against pathogens related to acne vulgaris and a low propensity for inducing antibiotic resistance. in clinical trials, sarecycline demonstrated clinical efficacy in reducing inflammatory acne lesions as early as three weeks and reduced truncal (back and chest) acne. hormonal agents in women, the use of combined birth control pills can improve acne. these medications contain an estrogen and a progestin. they work by decreasing the production of androgen hormones by the ovaries and by decreasing the free and hence biologically active fractions of androgens, resulting in lowered skin production of sebum and consequently reduce acne severity. first-generation progestins such as norethindrone and norgestrel have androgenic properties and may worsen acne. although oral estrogens decrease igf-1 levels in some situations, which could theoretically improve acne symptoms, combined birth control pills do not appear to affect igf-1 levels in fertile women. cyproterone acetate-containing birth control pills seem to decrease total and free igf-1 levels. combinations containing third- or fourth-generation progestins, including desogestrel, dienogest, drospirenone, or norgestimate, as well as birth control pills containing cyproterone acetate or chlormadinone acetate, are preferred for women with acne due to their stronger antiandrogenic effects. studies have shown a 40 to 70% reduction in acne lesions with combined birth control pills. a 2014 review found that oral antibiotics appear to be somewhat more effective than birth control pills at reducing the number of inflammatory acne lesions at three months. however, the two therapies are approximately equal in efficacy at six months for decreasing the number of inflammatory, non-inflammatory, and total acne lesions. the authors of the analysis suggested that birth control pills may be a preferred first-line acne treatment, over oral antibiotics, in certain women due to similar efficacy at six months and a lack of associated antibiotic resistance. in contrast to combined birth control pills, progestogen-only birth control forms that contain androgenic progestins have been associated with worsened acne. antiandrogens such as cyproterone acetate and spironolactone can successfully treat acne, especially in women with signs of excessive androgen production, such as increased hairiness or skin production of sebum, or scalp hair loss. spironolactone is an effective treatment for acne in adult women. unlike combined birth control pills, it is not approved by the united states food and drug administration for this purpose. spironolactone is an aldosterone antagonist and is a useful acne treatment due to its ability to additionally block the androgen receptor at higher doses. alone or in combination with a birth control pill, spironolactone has shown a 33 to 85% reduction in acne lesions in women. the effectiveness of spironolactone for acne appears to be dose-dependent. high-dose cyproterone acetate alone reportedly decreases acne symptoms in women by 75 to 90% within three months. it is usually combined with an estrogen to avoid menstrual irregularities and estrogen deficiency. the medication appears to be effective in the treatment of acne in males, with one study finding that a high dosage reduced inflammatory acne lesions by 73%. however, spironolactone and cyproterone acetate's side effects in males, such as gynecomastia, sexual dysfunction, and decreased bone mineral density, generally make their use for male acne impractical. pregnant and lactating women should not receive antiandrogens for their acne due to a possibility of birth disorders such as hypospadias and feminization of male babies. women who are sexually active and who can or may become pregnant should use an effective method of contraception to prevent pregnancy while taking an antiandrogen. antiandrogens are often combined with birth control pills for this reason, which can result in additive efficacy. the fda added a black-box warning to spironolactone about possible tumor risks based on preclinical research with very high doses (>100-fold clinical doses) and cautioned that unnecessary use of the medication should be avoided. however, several large epidemiological studies subsequently found no greater risk of tumors in association with spironolactone in humans. conversely, strong associations of cyproterone acetate with certain brain tumors have been discovered and its use has been restricted. the brain tumor risk with cyproterone acetate is due to its strong progestogenic actions and is not related to antiandrogenic activity nor shared by other antiandrogens. flutamide, a pure antagonist of the androgen receptor, is effective in treating acne in women. it appears to reduce acne symptoms by 80 to 90% even at low doses, with several studies showing complete acne clearance. in one study, flutamide decreased acne scores by 80% within three months, whereas spironolactone decreased symptoms by only 40% in the same period. in a large long-term study, 97% of women reported satisfaction with the control of their acne with flutamide. although effective, flutamide has a risk of serious liver toxicity, and cases of death in women taking even low doses of the medication to treat androgen-dependent skin and hair conditions have occurred. as such, the use of flutamide for acne has become increasingly limited, and it has been argued that continued use of flutamide for such purposes is unethical. bicalutamide, a pure androgen receptor antagonist with the same mechanism as flutamide and with comparable or superior antiandrogenic efficacy but with a far lower risk of liver toxicity, is an alternative option to flutamide in the treatment of androgen-dependent skin and hair conditions in women. clascoterone is a topical antiandrogen that has demonstrated effectiveness in the treatment of acne in both males and females and was approved for clinical use for this indication in august 2020. it has shown no systemic absorption or associated antiandrogenic side effects. in a small direct head-to-head comparison, clascoterone showed greater effectiveness than topical isotretinoin. 5α-reductase inhibitors such as finasteride and dutasteride may be useful for the treatment of acne in both males and females but have not been adequately evaluated for this purpose. moreover, 5α-reductase inhibitors have a strong potential for producing birth defects in male babies and this limits their use in women. however, 5α-reductase inhibitors are frequently used to treat excessive facial/body hair in women and can be combined with birth control pills to prevent pregnancy. there is no evidence as of 2010 to support the use of cimetidine or ketoconazole in the treatment of acne. hormonal treatments for acne such as combined birth control pills and antiandrogens may be considered first-line therapy for acne under many circumstances, including desired contraception, known or suspected hyperandrogenism, acne during adulthood, acne that flares premenstrually, and when symptoms of significant sebum production (seborrhea) are co-present. hormone therapy is effective for acne both in women with hyperandrogenism and in women with normal androgen levels. azelaic acid azelaic acid is effective for mild to moderate acne when applied topically at a 15–20% concentration. treatment twice daily for six months is necessary, and is as effective as topical benzoyl peroxide 5%, isotretinoin 0.05%, and erythromycin 2%. azelaic acid is an effective acne treatment due to its ability to reduce skin cell accumulation in the follicle and its antibacterial and anti-inflammatory properties. it has a slight skin-lightening effect due to its ability to inhibit melanin synthesis. therefore, it is useful in treating individuals with acne who are also affected by post-inflammatory hyperpigmentation. azelaic acid may cause skin irritation. it is less effective and more expensive than retinoids. azelaic acid also led to worse treatment response when compared to benzoyl peroxide. when compared to tretinoin, azelaic acid makes little or no