Use of Oral Contraceptives for Management of Acne Vulgaris and Hirsutism in Women of Reproductive and Late Reproductive Age

DOI: https://doi.org/10.5114/pm.2018.74895 Menopause Rev 2018; 17(1): 1-4 FEATURED PAPER

Use of oral contraceptives for management of acne vulgaris and hirsutism in women of reproductive and late reproductive age

Radosław Słopień, Ewa Milewska, Piotr Rynio, Błażej Męczekalski

Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poland

Abstract

Hormonal contraception in both reproductive and late reproductive age, as well as contraceptive action, is used also for other indications like dysmenorrhoea, menstrual disorders, endometriosis, acne vulgaris, and hirsutism. Acne vulgaris and hirsutism are important signs related to hyperandrogenaemia and present a serious medical problem for the patients and a challenge for medical doctors in terms of effective treatment. The application of hormonal contraception to treat acne vulgaris and hirsutism requires knowledge of the mechanism of antiandrogenic actions and the possible contraindications and complications. These data are presented in this review.

Key words: hormonal contraception, acne, hirsutism.

Introduction Hormonal contraception Hormonal contraception, as well as contraceptive Hormonal contraception consists of combined hor- action, is used also for other indications like dysmen- monal contraception and progestin-only contraception. orrhoea, menstrual disorders, endometriosis, acne Combined hormonal contraception consists of two vulgaris, and hirsutism [1]. According to epidemiologi- components: oestrogen and progestin, and is marketed cal data, hirsutism affects 5-15% [2] and acne affects in the form of pills, patches, and vaginal rings. Progestin 6-55% [3] of the female population. Both hirsutism and only contraception is marketed in the form of pills, in- acne are signs of hyperandrogenaemia [4] but are not jections, intrauterine devices, and implants. Combined always related to abnormal hormonal background [5]. contraception may have a beneficial impact in the Among the causes of hyperandrogenaemia polycystic treatment of skin changes; progestin-only contracep- ovary syndrome, hyperthecosis, adrenal hyperplasia, tion may not help in the treatment of skin problems obesity, Cushing syndrome, androgen secreting ovar- and may even worsen the state of the skin [10]. ian and adrenal tumours, and liver insufficiency are re- The oestrogen components of combined contracep- ported [4]. These are related to increased androgen syn- tion are ethinyl oestradiol and oestradiol valerate. The thesis or impaired androgen inactivation. Although the oestrogen content of the contraceptive combined pill is pathogenesis of acne and hirsutism is multifactorial, it very small in relation to the oestrogen content of the is usually related to the intracrine synthesis of active pills produced in late 1950s and 1960s. The decrease of androgens in the skin. Sebaceous glands and hair fol- oestrogen compound caused an increase of the impor- licles act as independent endocrine organs and respond tance of the progestin compound [11]. to the different levels of androgens [6-8]. Progestins in contraceptive pills may be divided into The androgens synthesised by adrenal glands and two groups: 17-OH progesterone derivates and 19-nort- ovaries are converted in enzymatic reactions in seba- estesterone derivates. Among 17-OH progesterone ceous glands and hair follicles into dihydrotestoster- derivates nomegestrol, medroxyprogesterone acetate, one (DHT). Dihydrotestosterone is 5 to 10 times more cyproterone acetate, and chlormadinone acetate are potent androgen receptor agonist than testosterone. used. Among 19-nortesterone derivates there are three DHT is synthesised from testosterone in the presence generations that differ in relation to antigonadotropic, of 5α-reductase [6]. Intracrine synthesis and possible progesteronic, and androgenic properties [12]. First- oversensitivity of the sebaceous gland and hair follicles generation progestins have both progesterone and an- to androgens explains why the women affected by acne drogen receptor affinity, while second-generation pro- and hirsutism may have normal androgen levels [9]. gestins are more progestagenic and less androgenic.

Corresponding author: Błażej Męczekalski, Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Submitted: 23.01.2018 Polna 33, 60-135 Poznan, Poland, e-mail: [email protected] Accepted: 31.01.2018

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Third-generation progestins are strong progesterone acetate, norgestimate, chlormadinone acetate, dro- agonists with even less androgenic activity. Typical spirenone, dienogest, and cyproterone acetate [1]. first- and second-generation progestins used in clini- Cyproterone acetate (2 mg of cyproterone acetate cal practice are norethisterone and levonorgestrel re- and 0.35 of ethinyl oestradiol) after 3 months of treat- spectively. Third-generation progestins include norges- ment caused subjective improvement in hirsutism in timate, gestodene, and desogestrel. Also there are also 83%, improvement in trichoscopy in 77%, visible im- so-called fourth-generation progestins, designed to be provement in acne in 40%, and very good cosmetic without androgenic properties. The first of these is dro- effect in 26% of patients. 86% of patient finished the spirenone, which is an antimineralocorticoid spironol- study, which suggests very good compliance and toler- actone derivate [13]. The second is dienogest, which is ability [18]. In a comparative study cyproterone acetate structurally related to 19-nortestesterone [14]. showed the stronger antiandrogen activity than drospirenone after 12 months of therapy (there was no dif- ference after 6 months of therapy) [19]. Late reproductive age and combined Chlormadinone acetate (2 mg of chlormadinone ac- contraception etate and 0.03 mg of ethinyl oestradiol) was effective in the treatment of mild to moderate acne and hirsutism Combined contraception may be used in women in [20], caused visible improvement in hirsutism and seb- late reproductive age without smoking, hypertension, orrhoea after 12 months of treatment [21], improve- 2 and BMI higher than 35 kg/m . In this group, higher risk ment of acne after 3, 6, and 12 months of treatment of cardiovascular disease and brain stroke should be [22], and a relevant decrease of percentage of patients kept in mind. In these women the lowest dose of ethinyl suffering from acne from 46.5% to 14.9% after 13 cycles oestradiol should be chosen. Apart from effective con- of treatment [23]. Chlormadinone acetate reduced the traception, these pills may ameliorate irregular menses, number of patients with skin problems (–55%), reduced heavy bleedings, climacteric symptoms, and bone den- the number of patients seeking dermatological treat- sity loss [11]. ment (–67%) and concealer cosmetics (–55%) and the Hirsutism and acne may occur for the first time or number of patients who felt that their self-esteem was aggravate in late reproductive age. This phenomenon is restricted due to skin problems (–67%) [24]. Chlorma- related to decrease of oestrogen level and no change in dinone acetate was more effective in the treatment of androgen secretion [10]. acne than levonorgestrel [1] and was more antiandrogenic than dienogest [25]. Drospirenone (3 mg of drospirenone and 0.02 mg Oral contraception: mechanisms of ethinyl estradiol) caused improvement in acne after of antiandrogenic action 6 months of treatment [26], significant improvement in the trunk acne (improvement > 50%) after 6 months of Antiandrogenic properties of combined contracep- treatment [27] and significant reduction of skin prob- tion are related to both components of the pill: oestro- lems treatment costs [28]. Drospirenone was more ef- gen and progestin. Oestrogen stimulates sex hormone fective in the treatment of acne than norgestimate [1]. binding globulin (SHBG) liver synthesis that in turn Drospirenone was more effective than chlormadinone reduces the amount of biologically active androgens, acetate in the treatment of skin changes such as seb- induces oestrogen receptor expression, and decreases orrhoea, acne, increased hair, hydration, homogeneity, gonadotrophin secretion that inhibits LH-related tes- and overall quality of the skin [29]. tosterone production by theca cells in the ovaries [15]. Dienogest significantly improved acne in 52% of Progestins block 5α-reductase activity, and decrease treated patients in one study [30] and in 66% of treat- testosterone receptor expression and gonadotrophin ed patients in another one [31] and its antiandrogenic (FSH, LH) synthesis [11]. 5α-reductase is responsible properties were also seen in a meta-analysis of 56 clini- for the conversion of testosterone into DHT. Both com- cal studies (2266 women treated) [32]. Dienogest was ponents of combined contraception lower the levels more antiandrogenic than both drospirenone and chlo- of adrenocorticotropic hormone (ACTH) that in conse- rmadinone acetate [25]. quence has inhibitory effect on adrenal androgenesis (dehydroepiandrosterone and dehydroepiandrosterone sulphate production) [16, 17]. Adding antiandrogen to oral contraceptives Adding an antioestrogen to an OC can be considered Results of clinical studies when initial response to 6 months of OC monotherapy The progestins of documented antiandrogenic ac- has been inadequate. Available antiandrogens are fol- tivity are as follows: levonorgestrel, norethindrone lowing: spironolactone (aldosterone and androgen re-

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ceptor antagonist; the mechanism of its action is based Hormonal tests are indicated in patients with acne on the competition with DHT for binding to the androgen resistant to treatment, in patients with hirsutism, and receptor and inhibition of enzymes involved in andro- in patients with menstrual disorders. In this case, the gen biosynthesis), cyproterone acetate (CPA – is a 17 hy- following hormonal tests should be done: follitropin droxyprogesterone derivative which competes with (FSH), lutropin (LH), total testosterone (T), sex hormone DHT for binding to the androgen receptor and reduces binding globulin (SHBG), dehydroepiandrosterone sul- serum LH and ovarian androgen concentrations) [33]. phate (DHEAS), 17OH-progesterone, thyrotropin (TSH), and prolactin (PRL) [42].

Oral contraception safety Contraindication to oral contraception The real nightmare for every clinician is a serious ad- verse event during therapy. From time to time medical According to WHO recommendations, the contrain- journals report a complication that is possibly related to dications to oral contraception are as follows: pregnan- the use of oral contraception. One of them was brain cy, breast feeding, history of deep venous thrombosis stroke in a 23-year-old fitness trainer after 3 weeks of and thromboembolic event, active liver disease, smok- oral contraception because of acne [34]. The patient ing after the age of 35 years, migraine, breast cancer, used 2 mg of cyproterone acetate and 0.35 of ethinyl hypertension, diabetes mellitus with vascular changes, oestradiol and had no other risk factors of thrombosis. and long-term immobilisation [43]. She was diagnosed with nonfluent aphasia and fully re- covered after thrombolytic treatment. Summary In summary the application of combined hormonal Oral contraception and the risk contraception in the treatment of acne vulgaris and hir- of thrombosis sutism improves the cosmetic situation and should be Oral contraception increases the risk of thrombo- considered as an effective option. This therapy should sis. The risk of thrombosis is highest during the first be applied after evaluation of the hormonal profile of year of use [35], and it depends on the dose of ethinyl the patient and exclusion of possible contraindications. oestradiol and the type of progestin used. Cyproterone In this setting hormonal therapy is relatively safe but acetate use is related to the highest risk of thrombosis: possible serious complications should be discussed relative risk of thrombosis during cyproterone acetate with the patient. use is 6.35 (95% CI: 5.09-7.93) with number needed to harm per year (NNH) 890 [36], the relative risk of brain stroke is 1.4 (95% CI: 0.97-2.03); NNH: 44,643 and Disclosure relative risk of heart infarction: 1.47 (95% CI: 0.83-2.61); Authors report no conflict of interest. NNH: 303,951 [37]. The relative risk of thrombosis during the use of norethisterone, levonorgestrel, and norgestimate is 2-3 with NNH: 2381-4762 [25]. Dienogest References has a similar risk profile to levonorgestrel [38]. The rela- 1. Arowojolu AO, Gallo MF, Lopez LM, et al. Combined oral contraceptive tive risk of thrombosis during the use of desogestrel, pills for treatment of acne. Cochrane Database Syst Rev 2012; 11: 7. 2. Williamson D, Gonzalez M, Finlay AY. The effect of hair loss on quality of gestodene, drospirenone, and contraceptive intravagi- life. J Eur Acad Dermatol Venereol 2001; 15: 137-139. nal rings was 4-6 with NNH: 952-1587 [39]. Chlormadi- 3. Azziz R. The evaluation and management of hirsutism. Obstet Gy- none acetate was reported to have a similar risk profile necol 2003; 101 (5 Pt 1): 995-1007. to desogestrel [40]. 4. Rosenfield RL. Clinical practice. Hirsutism. N Engl J Med 2005; 353: 2578- 2588. 5. Karrer-Voegeli S, Rey F, Reymond MJ, et al. Androgen dependence of hirsutism, acne, and alopecia in women: retrospective analysis of 228 Who should be treated with hormonal patients investigated for hyperandrogenism. Medicine 2009; 88: 32-45. contraception 6. Labrie F, Luu-The V, Labrie C, et al. Intracrinology and the skin. Hormone Res 2000; 54: 218-229. Hirsutism and acne vulgaris may be symptoms of 7. Lai JJ, Chang P, Lai KP, et al. The role of androgen and androgen recep- hormonal disturbances like polycystic ovary syndrome tor in the skin-related disorders. Arch Dermatol Res 2012; 304: 499-510. 8. Ebede TL, Arch EL, Berson D. Hormonal treatment of acne in women. or adrenal hyperplasia. Idiopathic hirsutism is also J Clin Aesthet Dermatol 2009; 2: 16-22. a serious medical problem. In the case of hormonal dis- 9. Thiboutot D, Chen W. Update and future of hormonal therapy in acne. turbances the use of hormonal contraception not only Dermatology 2003; 206: 57-67. improves the cosmetic situation of the patient but is 10. Tyler KH, Zirwas MJ. Contraception and the dermatologist. J Am Acad Dermatol 2013; 68: 1022-1029. also necessary to decrease the risks related to hyperan- 11. Sitruk-Ware R Hormonal contraception and thrombosis. Fertil Steril drogenaemia [41]. 2016; 106: 1289-1294.

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