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 11hydroxylase 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 (2.55 mg) or dexamethasone (0.250.75 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 23 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 (80100 g), which in practice would need to be balanced against the greater potential for adverse effects such as venous thromboembolism (VTE). Dosis rendah prednisolon (2,5-5 mg) atau dexametason (0m25-0,75 mg) diberikan saat malam hari cukup untuk menekan produksi androgen dan selanjutnya akan menghambat produksi sebum sampai 50% seiring dengan perbaikan akne. Pemeriksaan DHEAS secara periodik harus dilakukan untuk memantau efek glukokortikoid pada produksi androgen. Supresi adrenal dapat menjadi efek smaping dan ditemukan lebih banyak pada terapi dengan dexametason. Direkomendasikan untuk melakukan tes stimulasi hormon adrenorkortikotropik 2-3 bulan setelah awal terapi.

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. Kontrasepsi oral merupakan terapi utama untuk mengurangi produksi androgen dari ovarium. Kombinasi kontrasepsi oral yang menghasilkan estrogen dengan dosis yang cukup, akan mengurangi produksi sebum dan berpotensi untuk memperbaiki akne. Aksinya ganda, estrogen meningkatkan produksi hepatik hormon seks yang mengikat globulin, yang mengikat dan mengurangi kadar testoteron bebas yang bersirkulasi. Selain itu, estrogen menekan produksi androgen ovarium dengan menekan pelepasan gonadotrophin dari hipofisis, hal ini menghasilkan kadar serum androgen yang lebih rendah. 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 g 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. Thirdgeneration 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. Androgen Receptor Blockers Sebum production can be suppressed by anti-androgen agents including CPA, spironalactone, dropirenone and flutamide. The degree of reduction in seborrhea is drug and dose dependent.[106108] Cyproterone Acetate Cyproterone acetate is a progestional anti-androgen that directly inhibits the androgen receptor. While not available in the USA, it is widely prescribed in an oral contraceptiveformulation in Europe for the treatment of acne (Dianette [Schering Health Care Ltd, Sussex, UK] and Estelle 35 [Douglas Pharmaceuticals Ltd, Auckland, New Zeland]).[106108] Co-cyprindol combines 2 mg CPA with 35 g ethinyl estradiol and it has been suggested that the higher amount of estrogen in these agents carries a greater potential for VTE compared with conventional lower estrogen-containing COCs.[109] However, evidence for adverse effects of co-cyprindol concerning higher VTE risk suggests it is no greater than with third-generation COCs.[110,111] This would suggest that co-cyprindol can be continued safely once acne control has been achieved. A recent study also confirmed that increased VTE risk is less likely after prolonged use of second- and third-generation COCs.[111] Co-cyprindol reduces sebum production by no more than 30%, but its success in acne is enhanced by its direct effects on androgen-medicated comedogenesis.[112] It is as effective as oral tetracycline (1 g/day) given over a 6-month period, although it is slower in action.[113] It is therefore of potentially beneficial to females with acne are resistant to other therapies. An overall improvement in acne has been reported in up to 90% of patients treated with higher doses of CPA (50100 mg/day), with or without ethinyl estradiol.[114,115] The clinical

effectiveness of co-cyprindol can therefore be enhanced by prescribing an extra 50100 mg CPA from day 5 to 14 of themenstrual cycle. In males, 25 mg CPA has been demonstrated to improve acne, although its success is constrained by unacceptable feminization effects, such as reduced libido, gynecomastia and azoospermia. Therefore, it is only recommended as a treatment for female acne.[116] General side effects of CPA, although uncommon, include fatigue, headache, nausea, weight fluctuation, liver dysfunction and blood clotting abnormalities.[13] Spironalactone Spironalactone has inhibitory actions on both the androgen receptor and 5-reductase. It is an effective treatment for acne and can reduce sebum production by 3075% depending on the dose.[117120] It is usually prescribed at a dose of 50100 mg daily with meals, but many women with sporadic outbreaks can be successfully managed with as little as 25 mg daily.[120] Despite a consensus on the clinical benefit observed with spironalactone, there is a surprising paucity of data to confirm its efficacy in acne.[121] In one study of 85 women with acne, 93% demonstrated at least partial improvement in their acne, with 66% showing a marked improvement or complete clearance.[122] As with other hormonal therapies, response is slow and it may take up to 3 months of continuous treatment before any benefit is observed.[123] Spironalactone is not without side effects, although these are largely dose dependent. Menstrual irregularities, potential hyperkalemia, breast tenderness, fatigue, headache, fluid retention and, rarely, melasma have been observed. Animal studies have reported an association with breast carcinoma in rodents but this has not been replicated in human studies.[124] Owing to the potential for feminization effects, spironalactone should not be prescribed for male patients and females should be advised to avoid pregnancy owing to potential abnormalities to the male fetus. All patients should undergo regular monitoring of their electrolytes owing to the potassium-retaining effects on the kidney. Flutamide Flutamide is a nonsteroidal potent androgen antagonist, most routinely used in the treatment of prostate cancer. It has been demonstrated to be efficacious in treating androgen-mediated acne and hirsutism when administered at a dose of 125250 mg daily. Calaf et al. demonstrated significant reductions in acne severity score and hirsutism in 119 women with polycystic ovarian syndrome who were randomized to receive flutamide plus COC and compared with placebo at 6 and 12 months.[125] In a comparative trial between flutamide and spironalactone, Cusan et al. reported superior efficacy with flutamide with reducing total acne count and seborrhea level at 3 months.[126] However, given that spironalactone takes this

period to clinically improve acne, few conclusions can be drawn regarding the overall superiority of flutamide. Like all hormonal agents, it should not be prescribed for male patients and owing to the risks of teratogenicity, pregnancy should be avoided. In terms of safety, fatal hepatotoxicity has been reported with flutamide and, therefore, its use in acne is not widely advocated in the UK.[127] Initial warnings of hepatotoxicity were departed from patients using doses of 750 mg daily and reported prior to any dose-response studies being undertaken.[128] As a result, doses of 250500 mg daily became the primary recommendation for women with androgen excess.[129] Recent studies allude to the incidence of hepatic impairment being dose dependent in women with androgen excess, with minor toxicity occurring relatively frequently (~3%) in the dosing range of 250500 mg/day.[130,131] Whilst most cases are minor, prescribers should be aware that one case of fatal liver failure has been reported in a female taking no more than 250375-mg flutamide daily,[132] and many countries now prohibit the prescription of flutamide as a treatment for androgen-mediated acne and hirsutism. The use of lower doses of flutamide is currently under investigation. No cases of hepatic impairment with flutamide doses of 125 mg/day or less have been reported, and placebocontrolled data suggest that lower doses may be as effective as 250375 mg/day in antagonizing androgen production in females, especially when combined with a drospirenone-containing contraceptive.[133] However, given the severity of flutamide-related adverse events, the safety and efficacy of low-dose (50125 mg/day) flutamide must be demonstrated through large randomized multicenter trials. Therefore, authors the will not recommend the use of flutamide in females with androgen excess until such data are available. Isotretinoin Oral isotretinoin is a synthetic vitamin A analog that should be considered for all patients with moderate-or-severe recalcitrant acne, provided there are no contraindications. It is the only treatment that has an effect on all four major pathogenic factors involved in acne and is therefore, unsurprisingly, the most clinically effective anti-acne therapy available.[134
136]

Since its first approval for severe treatment-resistant acne in 1982, it has revolutionized the management of acne, producing long-term remission or significant improvements in many patients.[137] Isotretinoin decreases the size and secretion of the sebaceous gland, normalizes follicular keratinization and prevents comedogenesis, inhibits the growth of surface and ductal P. acnes via changes of the follicular milieu, and has anti-inflammatory effects.[134,136,138 141] During treatment, isotretinoin reduces sebum production by 90% or greater (within 6

weeks) and P. acnes populations decrease substantially.[141] However, both sebum and P. acnes levels increase upon cessation of treatment, albeit to a lesser extent.[142] This profound effect on sebaceous gland activity can be achieved in most patients with a dose of isotretinoin 0.51.0 mg/kg/day. A recent European Directive on isotretinoin prescribing has recommended a starting dose for all patients of 0.5 mg/kg/day, with the dose titrated to obtain a maximal early response offset against the development and tolerance of side effects.[143] Being lipophilic, it should be administered with food, which has been shown by pharmokinetic studies to double absorption.[144] A heavy alcohol intake should be avoided while on treatment as isotretinoin is metabolized by cytochrome P450 enzymes, which are induced by ethanol, resulting in reduced efficacy.[145] Whereas previously cumulative dosing has been advocated, it is now recommended that the duration and dose of isotretinoin should relate to the clinical response.[146] Most cases of acne correspond to a single 46-month therapeutic course; 85% of patients who receive a dose of 0.51.0 mg/kg/day are virtually clear of all of their acne by 16 weeks.[15] Some patients may tolerate and respond better to a longer course at a lower dose, especially mature adults with persistent and late-onset acne.[147,148] Demographic factors, such as age, sex and duration of acne, govern the rate of response and relapse.[15] A slow response is most commonly owing to the presence of macrocomedones (70%),[149] although other identifiable causes include associated hyperandrogenism, poor absorption of isotretinoin, colonization with Staphylococcus aureus, severe acne and unusual variants.[15,150] Differences in receptor sensitivity may also contribute to a slow response. Recurrence has been reported in up to 30% of patients and is most common in the first year after isotretinoin therapy,[151] with patients under 16 years of age and women being at the highest risk of relapse.[152] Maintenance with topical retinoid therapy may reduce the relapse rate by controlling microcomedo formation.[13] Approximately 6% of patients will experience a moderate-to-severe flare in their acne during the first few weeks of treatment. This is seen most commonly in patients with multiple macrocomedones and/or severe nodular acne.[153] Such flares can be avoided or controlled by overlapping the initiation of isotretinoin therapy with oral erythromycin for up to 2 months.[13] Oral tetracyclines should be avoided with isotretinoin as both can cause raised intracranial pressure. An alternative option is to start such patients at a lower isotretinoin dose (0.25 mg/kg/day) and titrate upwards over 46 weeks.[15] Light cautery or hyfrecation of macrocomedones and nodules prior to initiation may also reduce the potential for flaring.[154] If a severe flare should occur, isotretinoin should be temporarily discontinued and a 1421-day course of prednisolone prescribed at a dose of 0.51.0 mg/kg/day. The dose of steroid should then be gradually reduced over 6 weeks and isotretinoin reinstituted at a lower dose.[15]

Currently, isotretinoin is only licensed for the treatment of severe acne. However, in recent years, dermatologists have expanded their indications for isotretinoin and it is now frequently prescribed for patients with moderate inflammatory disease that has not responded to conventional therapy (topical agents and systemic antibiotics), acne that scars physically and/or psychologically and chronic acne prone to relapse. These indications remain outside the current product license. Over the years, isotretinoin has also been used 'off-license' to treat several other conditions with variable success, including severe acne rosacea, hidradenitis suppurativa, Gram-negative folliculitis and pyoderma faciale.[15] In 2006, a European Directive was implemented to harmonize generic prescribing and appropriate delivery of isotretinoin across the EU, and to minimize adverse effects including pregnancy.[143]Recommendations within the directive can be found in Box 2. The most significant adverse event associated with the administration of isotretinoin is teratogenicity. A Pregnancy Prevention Program has been advocated for all females of child-bearing potential and includes advice on education, therapy management and control of distribution of the drug. Educational aspects advise that both the patient and prescriber should understand the implications of teratogenicity the patient should accept detailed counseling from the prescriber before and during treatment and sign a consent form prior to initiation. Therapy management advises that medically supervised pregnancy testing is carried out prior to, throughout the month and 5 weeks after completion of treatment, and provides advice on contraception. Distribution control suggests that only 30 days of isotretinoin can be supplied to a female patient at one time and the validity of the prescription will last just 7 days.[15,143] Documented mandatory use of two forms of contraception while taking isotretinoin is standard practice in the USA as part of the National 'iPLEDGE' Registry,[101] but the recommendations set out by the European Directive state that physicians many exercise clinical judgment if they establish that the patient is not sexually active.[15,155] However, it is mandatory for clinicians to observe a negative pregnancy test result at each 4-weekly follow up visit, continue education, and record, as well as act upon, any change in circumstance. Pregnancy testing prior and 5 weeks after treatment cessation is mandatory. The Pregnancy Prevention Program suggests that patients should agree to use at least one, preferably two, forms of effective contraception (including a barrier method) before therapy is initiated. Teratogenicity is the most serious potential adverse effect of isotretinoin. Approximately 50% of pregnancies spontaneously miscarry, and of the remainder, half of the infants are born with cardiovascular or skeletal deformities.[156] Patients should be warned from the outset that termination will be recommended if they become pregnant while taking isotretinoin. Isotretinoin has many other adverse effects but most are predictable and rarely interfere with patient management.[137] Mucocutaneous dryness is the most common problem, including chelitis, facial and irritant dermatitis, vestibulitis and blepharoconjunctivitis. These are dose

dependent and rendered tolerable by modification of the dose plus symptomatic treatment (e.g., moisturizers and lip salves). Severe dermatitis should be treated with intermediatestrength steroid ointment combined with an antiseptic. Impetiginisation should be managed with oral anti-staphylococcal therapy such as flucloxacillin and/or topical 2% mupirocin ointment.[157] Very rarely, acne fulminans, characterized by destructive hemorrhagic lesions, leucocytosis, polyarthralgia and fever can be precipitated by isotretinoin.[158] Adverse psychiatric events including mood changes, depression and suicidal ideation have been reported in acne patients taking isotretinoin.[159161] Epidemiological studies performed by the US FDA in the USA found little or no increase in psychiatric disease including depression and suicide over the background prevalence in the adolescent population.[154,155] However, clinicians should be aware of a potential rare idiosyncratic reaction in some young, vulnerable patients, which could lead to mood changes and depressive symptoms during treatment with isotretinoin, based on a controlled study by Azoulay et al..[162] This is the first controlled case crossover study to demonstrate a statistically significant association between isotretinoin, acne and mood disturbance, with a reported relative risk of depression of 2.68 (95% CI: 1.033.89). It is therefore strongly advised for physicians to enquire about emotional change at each clinic visit. If significant depression is identified, referral to a psychiatrist is recommended and the drug stopped. A detailed history, including family history, of depression and suicide should be included in the pretreatment questionnaire for all patients considered for isotretinoin. Significant systemic effects are uncommon. Headaches may uncommonly be an early feature of benign intracranial hypertension.[163] Arthralgias may develop, particularly in those patients who participate in heavy and regular physical activity. Less common effects include gastrointestinal upset (diarrhea/colitis), paronychia, night blindness, urticaria, pyogenic granulomas and Achilles tendonitis.[164] There has been much debate in recent years as to the ideal serological monitoring strategy while on therapy. Elevations in lipids and liver function tests are observed in almost all patients and rapidly return to pretreatment levels after therapy has stopped.[165] A baseline assessment is essential, and the European Directive is prescriptive in suggesting that these blood tests should be repeated 1 month into treatment and every 3 months thereafter