PHARMACOTHERAPEUTICS J Korean Med Assoc 2017 August; 60(8):687-693 pissn 1975-8456 / eissn 2093-5951 https://doi.org/10.5124/jkma.2017.60.8.687 경구피임약의다양한적응증 김정숙 조시현 연세대학교의과대학강남세브란스병원산부인과 Clinical use of oral contraceptives Jeong Sook Kim, MD Sihyun Cho, MD Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea Since first introduction of oral contraceptive pills in 1960, with increased women s right of sexual decision, oral contraceptives had been used widely around the globe as a highly effective and safe contraceptive method. The physiological mechanisms of oral contraceptives were a reduced maturation of ovarian follicles and blocked ovulation to fertile women. Also, oral pills induce uterine endometrial decidualization, thickening of cervical mucus, disturbance of intrauterine sperm movement and embryo implantation. However, in addition to providing effective reversible contraception to fertile women, oral contraceptive pills offer various non-contraceptive benefits to numerous conditions. In this review, we summarize the list of currently available oral contraceptive pills in Korea and discuss non-contraceptive indications of oral contraceptives pills. Key Words: Contraceptives, oral; Non-contraceptive benefits 서론 경구피임약은 1960 년처음소개된이후, 여성의성적결 정권및여성인권신장의시대적사조와맞물려전세계의 가임기여성에게널리사용중이다. 경구피임약은난포의성 숙과배란을억제하여피임을유도하는안전한약제로복용 시자궁내막을탈락막화하고, 자궁경부점액의점성을증가 시켜자궁안에서정자의이동을방해하여피임에도움이되 는것으로알려져있다. 한편, 이러한피임효과외에도경구 피임제의비피임효과에대해서긍정적인평가가이어왔으 며, 실제로임상에서피임의목적외에다양한적응증으로 경구피임약을처방하고있다. 본논문에서는실제적으로국 Received: June 27, 2017 Accepted: July 11, 2017 Corresponding author: Sihyun Cho E-mail: sihyuncho@yuhs.ac Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 내에서사용되는경구피임제의간략한소개와선택시주의할점을다루고, 경구피임약의비피임적목적을위한다양한임상적적응증에대해살펴보고자한다. 경구피임제의종류와선택시고려사항 경구피임약의비피임적장점을나열하기전에먼저경구피임약에대해간략히살펴보고자한다. Table 1은국내에서시판중인경구피임제이다. 표에서제시된세대는개발된순서에따라나열한것으로 1세대의고용량의에스트로겐을함유한피임약 ( 에노비드 mestranol 150 μg + norethyndrel, 아나보라 ethinyl estradiol 50 μg + norethindrone acetate) 에비해점차적으로에스트로겐함량이낮아지고성분이 ethinyl estradiol에서 natural estrogen으로바뀌고있음을알수있다. 프로게스테론도 1세대에비해 2세대는 levonorgestrel, norgestrel로바뀌면서반감기는길어졌으나 androgenic activity가있 경구피임제의비피임적활용방안 687
J Korean Med Assoc 2017 August; 60(8):687-694 Table 1. Usable combined oral contraceptives in clinic Generation Name Estrogen (mg) Progestin (mg) Phase Pharm aceuticals 2nd ALESSE Ethinyl estradiol 0.02 Levonorgestrel 0.1 1 Phase 7 (21/7) ILDONG Minivlar Ethinyl estradiol 0.03 Levonorgestrel 0.15 1 Phase 7 (21/7) DONG-A Sexcon Ethinyl estradiol 0.03 Levonorgestrel 0.15 1 Phase 7 (21/7) CROWN Triquilar Ethinyl estradiol 0.03/0.04/0.03 Levonorgestrel 0.05/0.075/0.125 3 Phase 7 (6/5/10) DONG-A 3rd Mercilon Ethinyl estradiol 0.02 Desogestrel 0.15 1 Phase 7 (21/7) Alvogen Meliane Ethinyl estradiol 0.02 Gestodene 0.075 1 Phase 7 (21/7) DONG-A SENSLIBE Ethinyl estradiol 0.02 Gestodene 0.075 1 Phase 7 (21/7) Kwangdong Myvlar Ethinyl estradiol 0.03 Gestodene 0.075 1 Phase 7 (21/7) DONG-A Minulet Ethinyl estradiol 0.03 Gestodene 0.075 1 Phase 7 (21/7) ILDONG 4th Yaz Ethinyl estradiol 0.02 Drospirenone 3 1 Phase 4 (24/4) Bayer Yasmin Ethinyl estradiol 0.03 Drospirenone 3 1 Phase 7 (21/7) Bayer Qlara Ethinyl valerate 3/2/2/1 Dienogest Currently available combined oral contraceptives are classified in a variety of formulations, containing both estrogen and progestin. Doses of component hormones also vary among products, and some pills are monophasic (delivering the same dose of hormones each day) while others are multiphasic (doses vary each day). 12주이내에는 1년간만명당 40-65명으로정맥혈전색전증발생이증가하므로주의해야한다. 한편 dienogest 제제를포함한 4세대경구피임제는 2세대경구피임약과비슷한혈전색전증발생률을보이고부작용도덜한것으로보고되었다 [4]. 대한산부인과학회에서발행한경구피임제복용안내서에따르면, 경구피임약의사용에앞서반드시임신과출산, 수유여부를확인해야하고유방암, 간암, 간염, 뇌졸중, 심근경색, 다리혹은폐의혈전증, 고령, 당뇨및합병증여부, 고혈압, 고지혈증, 비만, 흡연여부, 두통및전조증상동반유무, 전신홍반성루프스, 향후수술예정유무, 항결핵약중 rifampin 복용유무, 항전간제, 사람면역결핍바이러스항바이러스제복용유무를확인해야한다고제시하고있다 (Supplementary Table 1). 는부작용이보고된바있다. 3세대에들어 gestodene, deso-gestrel, norgestimate가 2세대에비해 androgenic effect를감소하면서강화된 progesterone effect를보였으나여전히 androgenic effect는남아있었다. 이에비해 4세대에나온 drospirenone 제제는 spironolactone 에서유도된 analogue로 anti-androgenic 및 antimineralocorticoid effect 를동시에나타내어체중증가를 억제하고여드름을억제하는효과가있는것으로보고되고있다. 그러나최근국내에서 drospirenone 제제를포함한경구피임약을복용한 20대여성의정맥혈전색전증발생으로인한사망사고로 3, 4세대경구피임약의안정성문제가다시도마위로오르고있다 [1-3]. 프로게스테론의종류에따라 2세대경구피임제보다 3, 4세대경구피임제에서정맥혈전색전증발생이증가하는것을알수있다 [3]. 정맥혈전색전증은경구피임제사용시작후첫 3개월에가장위험성이높다. 비임신시경구피임제비복용자는 1년간만명당 1-5명의정맥혈전색전증이발생하는데비해경구피임제복용시는 1년간만명당 3-9명이발생한다. 따라서경구피임제처방할때에는정맥혈전색전증발생위험이증가하는것을반드시환자에게설명해야한다. 또한임신중에는 1년간만명당 5-20명, 출산후 1. 월경곤란증, 자궁내막증으로인한골반통월경곤란증은월경을하는젊은여성의 90% 까지호소하는흔한증상이다. 이는월경시자궁내막에서분비되는프로스타글란딘에의해자궁수축이이루어질때발생하는통증인데, 이는프로스타글란딘이자궁의비정상적인수축, 자궁내압력증가, 자궁내혈관수축, 통증수용체를증가하여통증에대한민감도증가및자궁근육의허혈로일어나는것으로보고된바있다 [5]. 경구피임약을복용하면프로스타글란딘의발생을줄여월경곤란증을완화시킬수있다. 이전연구로행해진무작위대조군실험에따르면경구피임약이대략 70% 정도의월경곤란증의경감을가져왔다 [6,7]. 무작위다기관연구에따르면 drospirenone 제제의경구피임약을 3회에서 6회월경주기간사용한경우월경곤란증과자궁내막증으로인한만성골반통증, 성교통을효과 688 대한의사협회지
Kim JS Cho S Non-contraceptive benefits of combined oral contraceptive pill 적으로감소시켰으며 [8], 24일사용후 4일휴약기를가지는치료보다 168일지속적사용후 4일휴약기를가진경우에유의미한월경곤란증감소를확인할수있었다 [9]. 경구피임제의사용은자궁내막증의재발방지에도효과가있는것으로알려져있다 [10]. 통상적으로가벼운정도의월경곤란증은하복부마사지나스트레칭, 온찜질로도효과적이며, 일차성월경곤란증조절을위해우선 nonsteroidal antiinflammatory drugs (NSAIDs) 를먼저사용한다. 일반적으로임상에서사용되는 NSAIDs 처방으로월경첫날부터 5일까지 melenamic acid 500 mg 3 times/day, naproxen 275-550 mg 2-4 times/day, ibuprofen 600-1,200 mg daily가있다. NSAIDs에반응하지않는월경곤란증이거나피임을동시에원하는경우병리적원인이없는월경곤란증에대해경구피임제를사용할수있다. 3회이상의월경주기동안 NSAIDs나경구피임제사용후에도월경통의호전이없는경우는이차성월경곤란증을의심하여야한다. 경구피임제를지속적으로사용하기어려운상황에서는 depot medroxyprogesterone acetate( 상품명사이아나 ) 와 progestin implant( 상품명임플라논 ), levonorgestrel IUD ( 상품명미레나 ) 가자궁내막증으로인한골반통증을경감시키는데효과적이다 [11-13]. 2. 월경과다월경과다는월경중인가임기여성의 10% 정도에서발생하는데, 한주기의월경량이 80 ml를초과하는경우를의미한다. 월경과다로인해환자에게빈혈을비롯한사회적, 경제적, 정신적불편감을초래할수있다. 국내시판중인복합경구피임제복용시 40-50% 정도의월경량감소효과를얻을수있는것으로알려져있다 [14-16]. 이는 cyclo-oxygenase 2 발현을억제하여월경량감소에기여하는것으로알려져있다 [17]. 최근도입된 4세대경구피임약중 dienogest와 estrogen valerate 성분의복합경구약제 ( 상품명클래라 ) 를 7회월경주기사용시월경량과다환자에서 88% 월경량감소효과가있는것으로보고된바있다. 클래라는월경량감소적응증이있는경구피임제이다 [18]. 프로제스틴단독경구호르몬제와비교한연구에 서도 dienogest 가함유된복합경구피임약을사용한그룹이월경량과다환자에서더짧은기간동안출혈이관찰되고, 효과적인월경량감소를보인다 [19]. 기질적원인이없는월경과다환자에서복합경구피임약의사용은가장경제적인첫일년간의치료방법이다. 이후지속되는월경량과다를치료하기위해서는 levonorgestrel IUD를이용하는것이효과적이며이것으로도조절이안된다면자궁내막소작술등의수술적방법을고려할수있다 [20]. 영국 NICE(National Institue for Health and Care Excellence) guideline에서는, 월경과다치료를위해 levon-orgestrel IUD를이용하는것이경구피임제보다처음시행할치료로권고하고있다. 3. 월경전증후군, 월경전불쾌장애 80-90% 대다수가임기여성이월경전오심, 더부룩함, 유방통증등의다양한월경전증상으로불편감혹은불쾌감을호소한다. 불편한정도에따라일상생활에지장을초래할정도의증상이동반될때월경전증후군혹은월경전불쾌장애로진단하고임상적인관심을가지고치료하게된다. 기존수행된연구에따르면복합경구피임제를복용하는여성에서월경전증후군이호전되지않는다고한다 [21]. 그러나, 최근소개된 4세대 drospirenone과 ethinyl estradiol 0.02 mg 제제 ( 상품명야즈 ) 의경우 3회월경주기동안복용시월경전불쾌장애를유의미하게호전시킨것으로보고되었다 [7,22]. 2006년미국식품의약국에서도이복합경구피임제를월경전불쾌장애치료제로승인하였다. 피임목적으로경구피임제를사용하는여성에서월경전불쾌장애를호소한다면 4세대 drospirenone과 ethinyl estradiol 0.02 mg을함유한제제 ( 상품명야즈 ) 를 24일간사용하고 4일간휴약기를가지는스케쥴로증상호전을유도할수있다 [23]. 4. 여드름, 다모증치료일반적으로복합경구피임제를사용할경우여드름과다모증을호전시키는것으로알려져있다. 이는복합경구피임제가황체형성호르몬에의한난소의안드로겐 (androgen) 생성을저하하고, 성호르몬결합단백 (SHBG) 이증가하여혈 경구피임제의비피임적활용방안 689
J Korean Med Assoc 2017 August; 60(8):687-694 중내안드로겐농도가감소하여생체이용이감소, 테스토스테론이디하이드로테스토스테론 (dihydrotestosterone) 으로변화하는데작용하는 5-α-reductase 활성억제, 그리고안드로겐수용체가차단되어호전되는것으로설명한다 [24,25]. 문헌상 4세대 drospirenone과 ethinyl estradiol 0.02 mg을함유한복합경구피임제가안드로겐수용체를차단하여남성화를억제하는효과가있고, 이로인해피지생성이줄고여드름과다모증에효과가있는것으로보고되었다 [26,27]. 위약대조군실험에서, 복합경구피임약은염증성및비염증성여드름을호전시키며, 이는복합경구피임약의종류에크게상관이없는것으로보인다 [28]. 5. 자궁내막증자궁내막증은자궁내막조직이자궁의내막이외의조직에서병리적으로확인될때진단되며, 특징적으로월경통, 성교통, 불임의증상을흔히동반하는질병이다. 월경혈의역류로인한자궁내막조직의이식, 체강상피화설이자궁내막증의기전으로알려져있다. 자궁내막증환자에서수술후경구피임제사용시, 월경통과성교통을감소시키며, 자궁내막증의발생및재발이감소하는것으로보고된바있다 [29]. 이는경구피임제사용시자궁내막조직이탈락막화되어위축을유도하게되며 [30], 자궁내막조직의세포자멸사를증가시키고, 국소적인방향화효소를억제하여통증이감소하는것으로여겨진다 [31]. 또한경구피임제사용시배란을억제하여자궁내막증의재발을억제할수있다 [32]. 이는수술후별다른치료없이자궁내막증을경과관찰하였을시재발률이 30-50% 가되며, 재발시재수술을시행하면난소의가임력이저하될가능성이커지므로경구피임제를사용하여자궁내막증의재발을낮출수있는것은임상적으로중요한의미를가진다. 한편, levonorgestrel IUD, GnRH agonist( 상품명 nafarelin, leuprolide, buerelin, goserelin, triptorelin) 를사용시에도자궁내막증의통증감소에효과가있으며재발을감소시키는것으로알려져있다 [33]. 자궁내막증의치료를위해, 수술후 GnRH agonist 사용시 30-50 pg/ml의낮은농도의에스트라디올의농 도를유지하면, 골다공증발생을억제하면서자궁내막증의재발과이로인한통증을감소할수있는것으로권고되고있다 [34]. 6. 다낭성난소증후군다낭성난소증후군은무월경혹은희발월경을동반하는 18-44세여성에서발생하는흔한내분비장애질환으로높은안드로겐수치를혈중내보이거나초음파상 10 mm 이하의난포가여러개보이는것을특징으로한다. 다낭성난소증후군에서경구피임제를사용하면, 황체형성호르몬, 난포자극호르몬에의한난포생성이억제되고, 성호르몬결합단백이증가하여혈중내안드로겐농도가감소하게되며, 테스토스테론이디하이드로테스토스테론으로변화하는데작용하는 5-α-reductase 활성을억제하게되어안드로겐의혈중농도를감소시키고, 자궁내막의주기적탈락을유도하여자궁내막을보호하는효과를얻을수있다. 앞서여드름과다모증치료에서언급한바와같이 4세대 drospirenone과 ethinyl estradiol 0.02 mg을함유한복합경구피임제가안드로겐수용체를차단하여남성화를억제하는효과가보고된바있다 [26,27]. 다낭성난소증후군의일차치료는생활습관을개선하여체중을감소하는것이다. 그리고인슐린저항성을개선하는메트포르민의사용을고려할수있다. 최근연구에의하면경구피임제와메트포르민을함께사용하는것이경구피임제단독사용보다인슐린저항성을개선하고안드로겐혈중농도를빠르게감소시키는것으로보고된바있다 [35]. 그러나다낭성난소증후군환자에서비만, 당뇨, 고혈압, 이상지질혈증이동반된경우가흔하므로경구피임제사용시정맥혈전색전증발생이증가할수있어주의하여야한다 [36]. 7. 자궁내막암, 난소암발병감소이전연구에서, 복합경구피임제를사용한여성에서자궁내막암과난소암발병이유의미하게감소하는것으로보고되었다 [37,38]. 복합경구피임제를복용한여성에서경구피임제의사용기간이길수록경구피임제의종류에상관없이난소암발병률이경구피임제를복용하지않는여성보다낮았고, 복용중단이후에도난소암발병감소효과가 10-20년 690 대한의사협회지
Kim JS Cho S Non-contraceptive benefits of combined oral contraceptive pill 간유지되었다 [39]. 5년간경구피임제를사용한경우 20%, 15년간사용한경우에는거의 50% 의상대위험비감소가관찰되었다. BRCA 유전자변이가있는환자에서도경구피임제복용시난소암발병률이그렇지않는군보다낮았다 [40- Supplementary Material Supplementary Table 1 Checklists for combined oral contraceptives. 42]. 이것은경구피임약복용시난소의배란을억제하여배 란시발생하는난소파열및이를수리하는과정이줄고, 난 소상피에대한뇌하수체호르몬작용이감소하기때문인것 찾아보기말 : 경구피임제 ; 비피임적사용 으로여겨진다 [43]. 자궁내막암역시복합경구피임제를사 용한기간이길수록암발병률이감소하였다 [44,45]. 자궁내 막암으로인한사망률역시경구피임약을복용한군에서유 의미하게감소하였다 [46]. Depot medroxyprogesterone 은 ORCID Jeong Sook Kim, http://orcid.org/0000-0003-3704-8852 Sihyun Cho, http://orcid.org/0000-0003-2718-6645 자궁내막의탈락을유도하여경구피임제와비슷한정도로 자궁내막암의발병을낮추었다 [47]. 자궁내막증식증이세포의핵이상을동반하지않은경우, levonorgestrel IUD를사용하면 96% 에서자궁내막증식증이치료되었다 (regression in 96%) [48]. 자궁내막암의전암병변으로여겨지는세포의핵이상을동반한복합자궁내막증식증에서 levonorgestrel IUD( 상품명미레나 ) 사용에대해서결론내리기에는아직더많은연구가필요한실정이며아직까지는자궁내막증식증에대한미레나사용적응증이없다. 결론 지금까지경구피임제가피임이외에도다양한임상적치료효과를가진경제적이고효율적인약제임을살펴보았다. 물론, 아직논란이되고있는경구피임제사용부분에대해서는향후수행할연구가필요한실정이나, 임상의로경구피임제의득과실을가려비피임적목적을위해서적절하고안전하게활용할수있어야할것이다. Acknowledgement This study was supported by research funds of the Ministry of Health and Welfare. REFERENCES 1. Boschitsch E, Skarabis H, Wuttke W, Heithecker R. The acceptability of a novel oral contraceptive containing drospirenone and its effect on well-being. Eur J Contracept Reprod Health Care 2000;5 Suppl 3:34-40. 2. Lidegaard O, Nielsen LH, Skovlund CW, Skjeldestad FE, Lokkegaard E. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9. BMJ 2011; 343:d6423. 3. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of combined oral contraceptives and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ 2015;350:h2135. 4. Dinger J, Mohner S, Heinemann K. Cardiovascular risks associated with the use of drospirenone-containing combined oral contraceptives. Contraception 2016;93:378-385. 5. Lethaby A, Duckitt K, Farquhar C. Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. Cochrane Database Syst Rev 2013;(1):CD000400. 6. Hendrix SL, Alexander NJ. Primary dysmenorrhea treatment with a desogestrel-containing low-dose oral contraceptive. Contraception 2002;66:393-399. 7. Winkler UH, Ferguson H, Mulders JA. Cycle control, quality of life and acne with two low-dose oral contraceptives containing 20 microg ethinylestradiol. Contraception 2004;69: 469-476. 8. Tanaka Y, Mori T, Ito F, Koshiba A, Kusuki I, Kitawaki J. Effects of low-dose combined drospirenone-ethinylestradiol on perimenstrual symptoms experienced by women with endometriosis. Int J Gynaecol Obstet 2016;135:135-139. 9. Machado RB, Pompei LM, Badalotti M, Ferriani R, Cruz AM, Nahas E, Maia H Jr. Effects of an extended flexible regimen of an oral contraceptive pill containing 20 μg ethinylestradiol and 3 mg drospirenone on menstrual-related symptoms: a randomised controlled trial. Eur J Contracept Reprod Health Care 2017;22:11-16. 경구피임제의비피임적활용방안 691
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