{"paper_id":"6a3ba63c-7c77-4887-a35d-fa81e71449d6","body_text":"1\nFEATURED PAPER\nDOI: https://doi.org/10.5114/pm.2018.74895\nMenopause Rev 2018; 17(1): 1-4\nSubmitted: 23.01.2018 \nAccepted: 31.01.2018\nIntroduction\nHormonal contraception, as well as contraceptive \naction, is used also for other indications like dysmen-\norrhoea, menstrual disorders, endometriosis, acne \nvulgaris, and hirsutism [1]. According to epidemiologi-\ncal data, hirsutism affects 5-15% [2] and acne affects \n6-55% [3] of the female population.  Both hirsutism and \nacne are signs of hyperandrogenaemia [4] but are not \nalways related to abnormal hormonal background [5]. \nAmong the causes of hyperandrogenaemia polycystic \novary syndrome, hyperthecosis, adrenal hyperplasia, \nobesity, Cushing syndrome, androgen secreting ovar -\nian and adrenal tumours, and liver insufficiency are re-\nported [4]. These are related to increased androgen syn-\nthesis or impaired androgen inactivation. Although the \npathogenesis of acne and hirsutism is multifactorial, it \nis usually related to the intracrine synthesis of active \nandrogens in the skin.  Sebaceous glands and hair fol-\nlicles act as independent endocrine organs and respond \nto the different levels of androgens [6-8]. \nThe androgens synthesised by adrenal glands and \novaries are converted in enzymatic reactions in seba-\nceous glands and hair follicles into dihydrotestoster -\none (DHT). Dihydrotestosterone is 5 to 10 times more \npotent androgen receptor agonist than testosterone. \nDHT is synthesised  from testosterone in the presence \nof 5α-reductase [6]. Intracrine synthesis and possible \noversensitivity of the sebaceous gland and hair follicles \nto androgens explains why the women affected by acne \nand hirsutism may have normal androgen levels [9]. \nUse of oral contraceptives for management of acne vulgaris and hirsutism  \nin women of reproductive and late reproductive age\nRadosław Słopień, Ewa Milewska, Piotr Rynio, Błażej Męczekalski\nDepartment of Gynecological Endocrinology, Poznan University of Medical Sciences, Poland\nAbstract\nHormonal contraception in both reproductive and late reproductive age, as well as contraceptive action, is \nused also for other indications like dysmenorrhoea, menstrual disorders, endometriosis, acne vulgaris, and hir-\nsutism. Acne vulgaris and hirsutism are important signs related to hyperandrogenaemia and present a serious \nmedical problem for the patients and a challenge for medical doctors in terms of effective treatment. The ap-\nplication of hormonal contraception to treat acne vulgaris and hirsutism requires knowledge of the mechanism \nof antiandrogenic actions and the possible contraindications and complications. These data are presented in \nthis review.\nKey words: hormonal contraception, acne, hirsutism.\nHormonal contraception\nHormonal contraception consists of combined hor -\nmonal contraception and progestin-only contraception. \nCombined hormonal contraception consists of two \ncomponents: oestrogen and progestin, and is marketed \nin the form of pills, patches, and vaginal rings. Progestin \nonly contraception is marketed in the form of pills, in-\njections, intrauterine devices, and implants. Combined \ncontraception may have a beneficial impact in the \ntreatment of skin changes; progestin-only contracep-\ntion may not help in the treatment of skin problems \nand may even worsen the state of the skin [10]. \nThe oestrogen components of combined contracep-\ntion are ethinyl oestradiol and oestradiol valerate. The \noestrogen content of the contraceptive combined pill is \nvery small in relation to the oestrogen content of the \npills produced in late 1950s and 1960s. The decrease of \noestrogen compound caused an increase of the impor-\ntance of the progestin compound [11]. \nProgestins in contraceptive pills may be divided into \ntwo groups: 17-OH progesterone derivates and 19-nort-\nestesterone derivates. Among 17-OH progesterone \nderivates nomegestrol, medroxyprogesterone acetate, \ncyproterone acetate, and chlormadinone acetate are \nused. Among 19-nortesterone derivates there are three \ngenerations that differ in relation to antigonadotropic, \nprogesteronic, and androgenic properties [12]. First-\ngeneration progestins have both progesterone and an-\ndrogen receptor affinity, while second-generation pro-\ngestins are more progestagenic and less androgenic. \nCorresponding author: \nBłażej Męczekalski, Department of Gynecological Endocrinology, Poznan University of Medical Sciences, \nPolna 33, 60-135 Poznan, Poland, e-mail: blazejmeczekalski@yahoo.com\n\nMenopause Review/Przegląd Menopauzalny 17(1) 2018\n2\nThird-generation progestins are strong progesterone \nagonists with even less androgenic activity. Typical \nfirst- and second-generation progestins used in clini-\ncal practice are norethisterone and levonorgestrel re-\nspectively. Third-generation progestins include norges-\ntimate, gestodene, and desogestrel.  Also there are also \nso-called fourth-generation progestins, designed to be \nwithout androgenic properties. The first of these is dro-\nspirenone, which is an antimineralocorticoid spironol-\nactone derivate [13]. The second is dienogest, which is \nstructurally related to 19-nortestesterone [14].\nLate reproductive age and combined \ncontraception\nCombined contraception may be used in women in \nlate reproductive age without smoking, hypertension, \nand BMI higher than 35 kg/m\n2. In this group, higher risk \nof cardiovascular disease and brain stroke should be \nkept in mind. In these women the lowest dose of ethinyl \noestradiol should be chosen. Apart from effective con-\ntraception, these pills may ameliorate irregular menses, \nheavy bleedings, climacteric symptoms, and bone den-\nsity loss [11].  \nHirsutism and acne may occur for the first time or \naggravate in late reproductive age. This phenomenon is \nrelated to decrease of oestrogen  level and no change in \nandrogen secretion [10].\nOral contraception: mechanisms  \nof antiandrogenic action\nAntiandrogenic properties of combined contracep-\ntion are related to both components of the pill: oestro-\ngen and progestin. Oestrogen stimulates sex hormone \nbinding globulin (SHBG) liver synthesis that in turn \nreduces the amount of biologically active androgens, \ninduces oestrogen receptor expression, and decreases \ngonadotrophin secretion that inhibits LH-related tes-\ntosterone production by theca cells in the ovaries [15]. \nProgestins block 5α-reductase activity, and decrease \ntestosterone receptor expression and gonadotrophin \n(FSH, LH) synthesis [11]. 5α-reductase is responsible \nfor the conversion of testosterone into DHT. Both com-\nponents of combined contraception lower the levels \nof adrenocorticotropic hormone (ACTH) that in conse-\nquence has inhibitory effect on adrenal androgenesis \n(dehydroepiandrosterone and dehydroepiandrosterone \nsulphate production) [16, 17]. \nResults of clinical studies\nThe progestins of documented antiandrogenic ac-\ntivity are as follows: levonorgestrel, norethindrone \nacetate, norgestimate, chlormadinone acetate, dro-\nspirenone, dienogest, and cyproterone acetate [1]. \nCyproterone acetate (2 mg of cyproterone acetate \nand 0.35 of ethinyl oestradiol) after 3 months of treat-\nment caused subjective improvement in hirsutism in \n83%, improvement in trichoscopy in 77%, visible im-\nprovement in acne in 40%, and very good cosmetic \neffect in 26% of patients. 86% of patient finished the \nstudy, which suggests very good compliance and toler-\nability [18]. In a comparative study cyproterone acetate \nshowed the stronger antiandrogen activity than dro-\nspirenone after 12 months of therapy (there was no dif-\nference after 6 months of therapy) [19].\nChlormadinone acetate (2 mg of chlormadinone ac-\netate and 0.03 mg of ethinyl oestradiol) was effective in \nthe treatment of mild to moderate acne and hirsutism \n[20], caused visible improvement in hirsutism and seb-\norrhoea after 12 months of treatment [21],  improve-\nment of acne after 3, 6, and 12 months of treatment \n[22], and a relevant decrease of percentage of patients \nsuffering from acne from 46.5% to 14.9% after 13 cycles \nof treatment [23]. Chlormadinone acetate reduced the \nnumber of patients with skin problems (–55%), reduced \nthe number of patients seeking dermatological treat-\nment (–67%) and concealer cosmetics (–55%) and the \nnumber of patients who felt that their self-esteem was \nrestricted due to skin problems (–67%) [24]. Chlorma-\ndinone acetate was more effective in the treatment of \nacne than levonorgestrel [1] and was more antiandro-\ngenic than dienogest [25].\nDrospirenone (3 mg of drospirenone and 0.02 mg \nof ethinyl estradiol) caused improvement in acne after  \n6 months of treatment [26], significant improvement in \nthe trunk acne (improvement > 50%) after 6 months of \ntreatment [27] and significant reduction of skin prob-\nlems treatment costs [28]. Drospirenone was more ef-\nfective in the treatment of acne than norgestimate [1]. \nDrospirenone was more effective than chlormadinone \nacetate in the treatment of skin changes such as seb-\norrhoea, acne, increased hair, hydration, homogeneity, \nand overall quality of the skin [29].  \nDienogest significantly improved acne in 52% of \ntreated patients in one study [30] and in 66% of treat-\ned patients in another one [31] and its antiandrogenic \nproperties were also seen in a meta-analysis of 56 clini-\ncal studies (2266 women treated) [32]. Dienogest was \nmore antiandrogenic than both drospirenone and chlo-\nrmadinone acetate [25].\nAdding antiandrogen to oral \ncontraceptives\nAdding an antioestrogen to an OC can be considered \nwhen initial response to 6 months of OC monotherapy \nhas been inadequate. Available antiandrogens are fol-\nlowing: spironolactone (aldosterone and androgen re-\n\nMenopause Review/Przegląd Menopauzalny 17(1) 2018\n3\nceptor antagonist; the mechanism of its action is based \non the competition with DHT for binding to the androgen \nreceptor and inhibition of enzymes involved in andro-\ngen biosynthesis), cyproterone acetate (CPA – is a 17 hy-  \ndroxyprogesterone derivative which competes with \nDHT for binding to the androgen receptor and reduces \nserum LH and ovarian androgen concentrations) [33]. \nOral contraception safety\nThe real nightmare for every clinician is a serious ad-\nverse event during therapy. From time to time medical \njournals report a complication that is possibly related to \nthe use of oral contraception. One of them was brain \nstroke in a 23-year-old fitness trainer after 3 weeks of \noral contraception because of acne [34]. The patient \nused 2 mg of cyproterone acetate and 0.35 of ethinyl \noestradiol and had no other risk factors of thrombosis. \nShe was diagnosed with nonfluent aphasia and fully re-\ncovered after thrombolytic treatment.\nOral contraception and the risk  \nof thrombosis\nOral contraception increases the risk of thrombo-\nsis. The risk of thrombosis is highest during the first \nyear of use [35], and it depends on the dose of ethinyl \noestradiol and the type of progestin used. Cyproterone \nacetate use is related to the highest risk of thrombosis: \nrelative risk of thrombosis during cyproterone acetate \nuse is 6.35 (95% CI: 5.09-7.93) with number needed \nto harm per year (NNH) 890 [36], the relative risk of \nbrain stroke is 1.4 (95% CI: 0.97-2.03); NNH: 44,643 and \nrelative risk of heart infarction: 1.47 (95% CI: 0.83-2.61); \nNNH: 303,951 [37]. The relative risk of thrombosis dur -\ning the use of norethisterone, levonorgestrel, and norg-\nestimate is 2-3 with NNH: 2381-4762 [25]. Dienogest \nhas a similar risk profile to levonorgestrel [38]. The rela-\ntive risk of thrombosis during the use of desogestrel, \ngestodene, drospirenone, and contraceptive intravagi-\nnal rings was 4-6 with NNH: 952-1587 [39]. Chlormadi-\nnone acetate was reported to have a similar risk profile \nto desogestrel [40]. \nWho should be treated with hormonal \ncontraception\nHirsutism and acne vulgaris may be symptoms of \nhormonal disturbances like polycystic ovary syndrome \nor adrenal hyperplasia. Idiopathic hirsutism is also  \na serious medical problem. In the case of hormonal dis-\nturbances the use of hormonal contraception not only \nimproves the cosmetic situation of the patient but is \nalso necessary to decrease the risks related to hyperan-\ndrogenaemia [41]. \nHormonal tests are indicated in patients with acne \nresistant to treatment, in patients with hirsutism, and \nin patients with menstrual disorders. In this case, the \nfollowing hormonal tests should be done: follitropin \n(FSH), lutropin (LH), total testosterone (T), sex hormone \nbinding globulin (SHBG), dehydroepiandrosterone sul-\nphate (DHEAS), 17OH-progesterone, thyrotropin (TSH), \nand prolactin (PRL) [42]. \nContraindication to oral contraception\nAccording to WHO recommendations, the contrain-\ndications to oral contraception are as follows: pregnan-\ncy, breast feeding, history of deep venous thrombosis \nand thromboembolic event, active liver disease, smok-\ning after the age of 35 years, migraine, breast cancer, \nhypertension, diabetes mellitus with vascular changes, \nand long-term immobilisation [43].\nSummary\nIn summary the application of combined hormonal \ncontraception in the treatment of acne vulgaris and hir-\nsutism improves the cosmetic situation and should be \nconsidered as an effective option. This therapy should \nbe applied after evaluation of the hormonal profile of \nthe patient and exclusion of possible contraindications. \nIn this setting hormonal therapy is relatively safe but \npossible serious complications should be discussed \nwith the patient. \nDisclosure\nAuthors report no conflict of interest.\nReferences\n1. Arowojolu AO, Gallo MF , Lopez LM, et al. Combined oral contraceptive \npills for treatment of acne. Cochrane Database Syst Rev 2012; 11: 7.\n2. Williamson D, Gonzalez M, Finlay AY. The effect of hair loss on quality of \nlife. J Eur Acad Dermatol Venereol 2001; 15: 137-139.\n3. Azziz R. The evaluation and management of hirsutism. Obstet Gy-\nnecol 2003; 101 (5 Pt 1): 995-1007.\n4. Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med 2005; 353: 2578-\n2588. \n5. Karrer-Voegeli S,  Rey F ,  Reymond MJ,  et al. Androgen dependence of \nhirsutism, acne, and alopecia in women: retrospective analysis of 228 \npatients investigated for hyperandrogenism. 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