Medical knowledge | Dermatology » Phoebe Rich - Hormonal Contraceptives for Acne Management

Hormonal Contraceptives for Acne Management Phoebe Rich, MD Acne vulgaris affects 42 mii/ion p eople. more than hall ot whom are women otder than 25 years. Treatment tor acne includes oral and topicat antibiotics, retinoids. and hormonal tllerapy in 1/le torm ot oral contracoptives (OCs). OCs reduce acne lesions by increasing estrogen leve/s and sex hormone- binding gtobulins. and by decreasing free tes tosterone and androgen le ve/s Se veral scudies have shown thai drospirenone a p rogestin a vailab /e ;,, c e1rain OCs, minimizes tl>e potential negalive etfecc the progescin has on acne. Women with moderace acne vulgaris who s eek concraception and teenagers with acne who .refus e antibiotics or in whom topical anti• biotics are ineffeciive might be candidaces tor drospirenone-containing OCs. Cutis. 2008;81(suppl 1): 13-18 n the United States, ac.ne ;,ulgaris affecLs 42 mii• !ion jl<úplé, including 85% of <1dolescents, as well as 40% of men and 54% oí wmnrn olcler

rhnn 25 ye.irsu According ro Srern,} each y~ar more than 5 million prescriprions for oral antibiotics are dispensed, inc.luding 14 nlillion prescriptions for isotretinoin l Dt. fbch is C4incal Asscx:iale PtofesSOf of Oermatology at Oregon Health & Scia1lCe Unlversity, POJUMO, am.i has a private practice Ml Portland. Dr Rich recs Véd :io l~arit1rn frQn OrthoNeutrogeoa and is oo the advisory bcard for 3M Pnarmaceuticals; Al:ltxlqt Laboratories: Amgcn lnc: Ge11entech. tnc; Medl(:i$ Pharmaceuüca! Ccrpora:ion: Nolartis Pharmaceutica1s Corp()ratioo: a.nd Sc:hering• Pfough Corporation Shc lt!.s dooe cioical réSG"arch fo1 Al!Argan, lnc; Alt-ana: Barrier Therapeutics: 8avq.ri~1 Nci,áic: CentOCO< lnc; ~1~ Li:!OOlatories: OermTech lmernational. Int Oow Pharmace~tical Sciences, lnc; OUSA Fharmaceu!icas. Inc Galdcrma Laborntones LP; Gene!liech, lnc: Hm Oerm.-;oeuticals Inc lmcnó,s, Inc MacroChe<n; Medicis Fharmaceu!ical Corporation, McdiQuest Therapétrtics, lnc; Medivir:

Merz Pha~rra Nano8io Corporatioo.- · Neutrog,ena Corporation; Novartis Pharmaceu1ica1s Co1paratio:l; NovllTI Ftlarmacetdca1 Research Setvices; Pfl2~ loc; Pf()(ocure; $ctle(ing-Pfough Corpora:ion: Sneíef Laboratoríés, lr~c; $ylrlt)(); Teva Pharrr-acevticals; Tolmar Inc. Wamcr-LamOOtt Company; and xo,na She a1so has been a speaker tor 3M Pharmaccu!icals, CollaGenex PhArm,:l(;ét.Jhca!s Inc Connetics Corporaton, and r-&:warns Pharmaceut1c~1s CorpúratiOO. Acn ~ has a complex etiology. lt is an androgen• mcd iared disordcr Lhat involves "hnorma l kera• tinization, bacterial growrh, and immune,driven hypersensirivity. The condicion is aggravared by e xLrinsic faccors, inclu<ling srress, friction, oc.clusion by c.omedogenic producLs (~g, pmmides) med ic"rions (eg anabolic sreroids, am iepileptic dru!,ll, progc.stin,only conrrnceptives), medkal co nditions (eg, Cushing d isea,c), and possihly diet. Tre.atmems for acne include oral or topic,il imtihiorics ,md

retinoids and honn one therapy Oral ami • biotics arc comidercd firsr-line therapy for patiems with moderate to severc inflammm.ory (1cne ()ral isotretinoin is indk.ated for patienLs witl1 sevt!re noJu lar acne and c"ses re, istam to other treatmems, Long -cerm copical or oral antibio ric.s however, come with a price: pos.sible bactcrial rcsistance The goa l with hormone therapy is ro block hormonal effecr- (spironolactone) or to suppress hormon~ prod uclion (OCs). 45 Ornl contracepti ves (OCs) a re useful for women who a lso scck thc con rn,cepri ve benefits of rhe p ill. For reproduccive -aged wonu:n, a varit!ty o f conrrnceptives are available (Table 1). Wh en treating acnc , cstrogen is rhe benefic ial hormone, whereas a progcstin -only pill, which rends co exacerbate acne, should be avoided . OCs reduce acnc lcsions hy suppl ying estrogen and increasing sex hormone- binding globulin (SH BG), dec reasing free testoscerone, and suppressing ovar• i;m pro<luctio n of

an<lrogens.4 The overall chera-pcuLic effecL of O Cs in acnc is pmenri"lly brooghr abouc by ( 1) srimulacion of SH BG, wh ich dccrcascs restosrerone concentra tions; (2) inhibition o f 5 a,rcductasc, an cnzyme thm converts tescosce ro ne to d ihydro re.stosce ro ne (an activc androgen ln rhe skin; (3) dec reased production of ovarian androgens; ami ( 4) decre„sed pro<luction of adrenal androgem. Th is process rcsulLs in dccreased seh11m production a nd h air growth.r,• Th e Roles of Estrogen and Progestin Estroge.n in doses h igh er than Lhosc found in modern OCs suppresses sebu m an d, rhereiore, developmenc VOLllME $1 J/.NU4AY 2X 8 13 Hormoorl Cooiraceptil@s of ac.ne lesiom Throu~h the metabolizat ion of estrogen in the liver, this hormone also increases S HIK, . ln addirion, beca usc OCs suppre,,- the ovary, LCStostcro n e p ro <lucrio n is reduce.d Some progestins arc more androgenk rhan oth• ers, and rhose wirh androgrnic tenclencies may ex;icerh;1re

(1Cn e. Drospirenone, the prog<::st in in ce r, tain oc~ (o:Lhinyl esrrncliol (EE 20 µg/drospirenonc 3 mg [Yaz), EE 30 µ g/J rospirenone 3 mg [Yasminj), has lx){h anrimineralocorricoiJ ,inJ anriandrogenic cffccts, thus min imizin~ the poremially ncgative Table 1. Hormonal Contraceptives That Are Available in the United States Estrogen Combinations Monophasic Triphasic Extended cycle effecc tha t progcstins c;in have on acne. Transdermal patch Vaginal ring Progestin-Only Compounds lmplants levonorgestrel-releasing intrauterine system Oepot medroxyprogesterone acetale iníections ■ DRSP 3 mg/EE 20 µ g 24/ 4 COC Papules "e O .Q -.,3 ," ·-<t e „ .J O 0 How Effective Are DrospirenoneContaining OCs in Treating Acne? Srudies have shown that comhinacion OCs are parricularly effective in creating acnc. ln a multicencer. double-blind , randomizecl, placebo-controlb] study conducted ar 28 cemcrs in rhe United States, Maloney er a 1"·11 assessed the safery

,md efficac.y of an OC (EE 20 µ g/drospirennne 3 mg) administered in 6 trearmenc cyd esover 24 consecutive dars of activc treannenr followed by a 4-day honnone-free incerval, and compared ir wirh placebo in rhe treHtment of acne vulgaris. This íonnulation wis approvcd hy rhe US food and Drug Administration Pustules 0 ■ Open comedones Placebo Closed comedones -2 - 4 ~ „E "l5 z ·- .0 ::, .i:: e -6 P =.0 269 -8 P= .0269 (.) 1-1? - 12 P = .0076 , P = .0016 Figure 1. Change in adjusted rnean nurnber of lesions (papules, pustules, eper) and closed comedones) from baseline to end point (full analysis set). Tho P values show the difference between the DRSP 3 rng/EE 20 µg 24/4 COC and placebo groups. COC indica1es combined oraf contraceptive: DRSP drospirenone: EE, elhinyl estradiof Reprinled !rom Maloney JM , Lee-Rugh S. Kunz M, el al Orospirenone 3 mg/cthinylestradiof 20 1,g COC in the 1rea1ment of acne vufgarís: investigator and subject self-assessrnent

Poster presented a1: 55th Annual Clinical Meeting of the American College of Obstetricians and Gynecologists: May 5-9. 2007: San Diego, CA•0 Courtesy of Bayer HeallhCarc Pharmaceuticals. 14 CU il~., Hormooal Cootrnceptivcs 30 ■ DRSP 3 mg/EE 20 24/4 coc 25 µ,g 1 Placebo 20 15 10 5 Baseline Cycle 1 Cycle3 Cycle 6 End Point Treatment Cycle Flgure 2. Percentage of subjects ,ated as clear (score 0) or almost cloar (sco,e 1) on the investigators stalic global assessmen1 scale by treatment group and cycle (full analysis set). COC indicates combined oraf c-0ntraceptive: DRSP, drospirenone; EE, ethinyl ostradiol, Reprinted from Maloney JM, Kunz M, Lee-Rugh S, et al. Drospirenone 3 mg/ethinylestradiol 20 p.g COC in 1he freatment of acne vufgaris: lesion count ISGA Pos1e1 presen1ed at: 55th Annual Clinical Meeting ot the Ame1ican College of Obstetricians and Gynecologists: May 5-9. 2007: San Diego, CA · Counesy of Bayer HealthCare Pharmaceuticals. Íor the (Teacmenc of

acne vul~aris in Íl:m:1les ar lt-ast 14 ycars of age who have (eached menarche and want an OC for birth rnntml. T he study randomized 5J8 women to EE 20 µ g/drospirenonc J mg (n =l.70) or placelx, (n=268). Th e mean age of subjects was 25 years.10-11 Subjeccs were as~cs.~c<l at screen ing; at baseline during nmdomization; on d ay 15 (:!:3 days) of treat, ment cydes 1, , , and 6; and ar a follow-up visiL (clays 8- 15) after trcatmcnt wHs completed.°·11 The primary e.fficacy variables were percen tage change in inflammatory, noninflammatory, and toral lesion coun t~ Írom baseli 11e and percemage of subjects. classified as bavini::dem skin ~score O) or a lmosc-clear skin (score ! fon rhe 6-point inves, rigacors statk global assessmenc scale . Safety was assessed wirh changc, reporred in laboratory values (hematologic, blood chemistry, urinalysis) , <efirh physical ancl gynecologic examinations, and wiLh measurement o( vital signs. 1ll,u The baseline lesion count Vas compa

r-able betwecn subjects in the EE 20 µ g/drospirenone 3 mg and placebo groups. A sign ificanrly larger reduct ion in mean percencagc changc in inflamma tory, nonint1ammt1 tory, <1 11d tocal le.sio n Cú unt~ from baseline occurrcd in the EE 20 µg/drospirenone 3 mg group (P< .0001) (Figure 1) 10 Ad ver;e evencs wece consiscenc wirh hormonal co ntracept ive u:,e and Jid nor n1i,;e ,;;1fecy concerns. The EE 20 µ g/ drospircooru: 3 rng fonnulmion was rated by women as significan dy more effective than placebo for che rrearmenr of acne (P<.0001) A greaLer pmportion of womc:n were rnted as having significantly clearer or almost-clear skin by cydc 3 (Fi~>J.,re 2)1 These (indings were. consistenc with invesligmor a~sess-menr and rhe reducrion of lesion coums in subjects randomizecl tú thc OC. 1t was concluded thar this formulat ion of EE and drospirenonc is effective for women who have moderare acne vulgaris an<l wanL contra<.:epti<m u)1 1 Two double-blind, rnndom

i,ed , conrro lled trials were conducted to examine EE 20 µg/dmspirenone 3 mg vcrsus placebo in a tocal of 889 women. Trea tmem took place for 6 cyclcs consisring of 24 consecurive days of active creatmem followcd by a 4-day honnone-free phase. Subjec{s showed substamial improvem.ent in ir1ílamma tory1 non inffammatory, an d tocal lesion cowus (Table 2). 11 Dmspirenone Hormaoal Caotraceptive<s binds to che retin-angiorensin-a ldosrerone sysrem, blocks rhe aldosrerone receptor on the kidney, lesions (papules, pusrnles. and nodules) By cyde 9 1 inflammmory an<l noninflammmory lesions wcre rcJuccd by 73.5% and 50%, respectiveiy, in the EE 30 µ,g/drospirenone 3 mg group and by 75% and 60%, respecrively, in rhe EE J5 µ,g/cypro• terone 2 mg group. S uhjccts, Jermatologists, an<l gynecologists gave subjective rarings of exce.llenr, good, or moderate improvement in most cases ín and p romores excrerio n of so<liu m and wtiter, r.hus de(reasing hloating1 breast

tendernes:,, and water weighr gain. The 24/4 regimen wirh EE 20 µg/ drospirenone 3 mg extends the antimineralocorti• coic.1 an<l nntiandrogenic act iv ity hy 3 cfays, anJ thc 30-hour half-liíe of drospirenone exrends rh e progestogenic effecr rhrough rhe 4 days with hormone• free pilis. ln an earlier multicenter, doublc-bl ind, randonuzed srudy, van Vloren er al I J compared EE 30 µg/drospirenone 3 mg wirh EE 35 µg/cyprorer• eme 2 mg (Di,me-.,5; nor availahle in rhe UnitcJ States) over 9 trcatmenL cyclcs. Each cyclc comprised 21 consecucive days of acrive rreatment followed by a 7-day hormone-free incerval. T he study r,mdomized 128 women who had mild to moderare f-acial acne with or without seborrhea and/or h irsutism ro EE 30 µ.g/drospirenone 3 mg or EE 35 µg/cyprote rone 2 mg. The per prorocol Sél indudo::d 91 suhjccrs (EE 30 µg/drospi renonc 3 mg, n = 58; EE 35 µg/cypro rerone 2 mg, n = 33). End-of-srudy asse.ssmems of acne trearmem were mfJde by dermf)tologists,

gynecologists. ,md subjec ts T hc median arne lesion count dccrea,cJ in both both groups. Few cases were considered <1g, ~rnvared or unimproved. Thorneycrofr er al" conducted a double -blind study in 1154 women to compare the effic.acy and rolernhi lir.y of EE 30 µ,g/clrospirenone 3 mg (n = 5 68) with thos.:, of a rriphasic OC (EE 35 µg plus norgestimate 180/215/250 µg [Orth o Tri-Cyclen); n = 586) in treating acne v ulg <1ris. T hese p reptJrations were ad mi n isr.l!rt<l fo r 6 trcauucnl cytl<~ , cac h com„ prising 21 consecutive days of acrive treaunent followed by a 7-dfly hormone-free inrerva 1. Both OCs were comparnhle in decreasing inílamm.i to ry lesion counts. lnvt:SLigaLor and su6jec:L c-valuaLions also were comparable. Borh prepararions increased SHBG levels and decreased androgen levels, ,md both were well rolcrared in rhis group of wome::n wir.h mi ld to moderate acnc 14 treannent groups through cycle 9. Tora! acne lesion Who Qualifies and Does

Not Qualify coum was reduced by 62 .5% and 588% ín rhe EE ,0 µ,g/drospirenone .3 mg ancl EE , 5 µg/cyprotemne 2 mg groups, rcspcctivdy. Both prcparations were effecrive in reducing sebum produccion and hair growth on rhe upper lip and chin, resulred in a 3-fold increase in SH ti(;, and reducecl levds ofandrogcns and lut<:inhing hormone. n Boch trearmenrs proved beneficial in reduc.ing noninflammatory lesions (open and closed comednnes) fJncl inflammatory tor Acne Treatment With OCs Containing Orospirenone? Patiems who qualify must wam conrracepti on. They include hea lrhy nonsmoking women wirh reGtlcitrnnt lowc-r fac;, jawlinc-, anJ ncck acne, women wirh hyperandrogenic condit ions, women who have had difficulty adhering to an OC sched• ule hecause of untowarcl side cffocr.s from high c-strogcn levels buc who are- now w illing to cake Table 2. Efficacy Results for Acne Trials*12 Study 2 Study 1 Yazt Yaz (n = 228) Placebo (n -230) (n=218) Placebo (n= 213) Mean

baseline count 80 80 76 76 Mean absolute (%) reduction 33 (42%) 21 (25%) 33 (46%) 22 (31%} -( Total lesions ·Evalua:ed ai day 15 ot cyc1e 6, last observatoo carried 1orward for th;; 101s;1J-lo-t1ffal population tEthinyl estradic! 20 IJ.9/drosp renore -3 mg 16 ().fn~ l::!ormon::,i Co□ín=1ceptive« Figure 3. Wornan with chronic low-grade cystic acne Figure 4. Woman wilh low-grade acne and scarrjng " low-dose O C, women wl)() h,ive acne anJ pre- have been on topical ret inoids and anribiotics bur mcnsrrual dysphoric disorder, anJ teenagers wich are nor improv ing. These palic:nts ;ire good candi, cercain considerations (see below). datcs for an OC. Adding an OC would help mosr Patien~, who donor qualify include won,cn wirh a women wirh acne tha t is nm responding to standard conttaindica.tion to OC d,erapy, including d,mmho- oral or topical rherapy ln the aurhors experience, emholic disordeni, severe or uncont.mlled hyperten- when the acne firndly dears,

topical med icarions sion, ;11igraine wid) fo<.:al neurologic sympr()ms, some often ,ire no longcr necessary, proviJed the patiem malignancic~, ,md pregnancy; men: ancl heavy ~mok, remains on the OC. crs (c:15 c igarcttes per day) o ldcr than 3 5 years. \íomen With Low-Grade Acne- A 28-ycar-old Teenaicrs: Amibimics Versus OCs- ln the aurh ors hlack woman was treared with a course of isorretinoin expericn~e. many teenagers prefer OCs over anribiot- and now has acne scar, (Fi1,>ure 4) She lms low-grade ics. Those whn qualify for OC use may have pcrsisrenr acne, with occasional cystic l1=sions, usually not com-p,ipnlar, pusLular ,icne and may have nsed combination edonal She does not wanr ro wke ,mtibiotics bcc ause pro<lucrs without goo<l results. They nrny have some of recurring yeast infcctions Her skin is oily and subcystic acne ,md are candiclates for OCS hcc,inse rhey jecL to rnndom papules arnl pusrules She w,mts conwant co1uraception rraceprion. Ti, conrrol hcr acne,

this patiem would Teenagers Vho Fai/ Topic<Ú So!utions- Teenagers like something in addition ro h er current medication. wich rnx1ulocystic acne unresponsivc to rreannent An OC would be a suitable option. with minocycline, topical rer.inoids, and bcnzoyl per\íomen \íithAndrogenic Sym/>wms- A 24-year-old oxide are candi<lares for isocrecinoin but may want to woman wich acne, h irsutism, anc.J androgenic a lotry ocher producr, , including OCs, firsr They must pecia is bothe reJ hy acne and some facial hair, wanc contrncepcion an<l may experic-ncc moderace and her menses are irrcgu lar. For [hh pmient a symptoms rdared ro premenst.nrnl syndrome T hey workup is r~4uired to rulc out other serious Cúnd iwould benefü from isotretinoin but cleserve a Lrial tions There arc mnlciple signs of hyperandrogenism wirh an OC. lf the ecne has not improvecJ after sev- (ic, hirsurism, androgcnic alopecia, voice deepen-eral momh$ of add ing an OC 1> rheir acne regimen, ing, acanthnsis

nigricans), which also must be Lhen isocrerinoin c,m be startetÍ. addressed. Workup for rhis paticnr should induJe \íomen \íirli Homum(l/ly Driven Acne- Xlomen measuremenc of frcc and tocal ceswst.erone to rule who want conrraceprion and have acne that. is hor- out or cJia1,"1ose ovarian tmnors, dehydroepiandrosmonally drivcn also may be candidares for an d C re rone sulfate co idemify acJrenal problenL,, and Chmnic low-graJc acne, usually c ystic, affecting the 24-hour urine cortisol ro check for sif,,flS of C ushing lower face, jawline, anJ neck often re,ponds well discas~. ln addition, clinic,i l evaluarion is w,irninted ro hormonal rherapy (Figurc J). Other candicJares to check for pn lycysric ovary syn drome (PCOS), a arc women who wanr concraceprion and have 1nen - diagnosis establi,he<l by presence of hirsutism, acne, suual llares of acne. They are nonsmokers who are or male-parrern a lopcci;i toge the r with evidence frustrared wirh the chronic narure of their acne

and of anovulatinn ( <9 menstrual periods pe r y~ar nr VúLUMc 81 , ,IANUAnv 20W 17 Hormooal Contracep1ille.s cycles > 40 days). Hormone resring is relarively insensitive far che diagnosis of PCOS. l f this patiem is seeking comraccplion, " trial of an OC m;,y he won hwhile. Comment Alt.hough acne is considered a disordcr of atlokscems, íc persists in many parienrs older than 25 years Goulden and collcagucs! fountl thar 12% of rhe 427 women in rheir srudy populaLion cxpcrience<l adulLacnc. ln 82% of affected adults, persiscenr acne racher rhan late-onset acne was implicated. Acne may also result írom an androgcn <l isonler, wh ich c::m manifest as acne vulgaris, h irsutism, schorrhca, or androgcnic alnpecia. Several srudies have demonstrated the effeclivcncss of OCs in decreasing tora! acne lesion cow1cs and clin ical androgcnici ry. T he ir cff.::ctiveness lies ín part in cheir abiliL-y L0 dccrcasc androgc-n cxpression, ;m important facwr in che developmem of

acnc. Jf an OC Joes not provide adequire d earing, it can be combined with oth~r Hcn c or honnonr,I tremments as desc.ribed Alchough OCs do noc represcm first-line rhernpy or monotherapy, rhey can serve as a go<Xl solution for many patien ts with mil<l to moderare acne vulgaris. REFERENCES globulin an-d fre-e cescoster0nt!. Am J Obmit G ync:eol 987;1%:199-203. 10. M:-tlom:y JM, Lc,•c-Rugh S Kunz M, et al Drnspirenont: 3 1ni.?/e-thinylestradiol 20 pg in thc trcatmcm of acne vulg.iris: in vestigator and subj~1 $d f-Asse,,smc•nt Postcr prc:.,;c:ntcd at: 55th AnnuaJ C linkal Yteeling of lhc American CoUt:g.: of Obt ctrldms and Gynecologi:,cs; May 5-9, 2007: San Di,go, CA. 11. Maloncy JM, Kuni M, Lee,Rugh S, c-1 al f>rnspircnonc J mg/cthinylel:itr.idi<1I 20 Jlg COC in che creau11e1)L oí actlt. •ulgari~: lesion c<>unt, ISGA Posrer preserued ar: 55th iJmual Clinical Meeting uf rhc Amcncan Cunliffe WJ . Prcva,knce of fada,l "cnc in adults. J Am Arnd Dm naiol

1999;4 l: 1. Gouldon V, Scables ü l, C.ollcgcoí O bsmrician,andüynecúlogin<; May ,9, 2007; S:m Oicgo, C:A. 12. Yaz lpa<kage insert) Wsync, NJ: Bayer Heolth Care 577-580. 2. Ro;en MP, llrei,k,>pf DM, Nsg:nnsni M A mndomuod controllcxl trial of second, v~rsus thir<l, gt:nt!rHtinn orHl com raccptivcs m rhc tre.itmem of acne vu~aris Am ) Obscer ü~•ie<-ol. 200l; 188:1158-1160 3. Srern RS Medication and ntc<lic:-tl servk:c vtiliz3tion for :,cno 1995-1998. J Am Amd Dermatol 2000;4l: 1042-1048. 4. l laider A, Shaw JC Tre:-inm:nt nf :Jcnc vulgaris )/MA 2004;292:7l6-i35. • -1 18 O.Jls-t 5. Jatne-s WO C lilical pnttlic:t: Acn c N Engl J Med 2005;352:1463- 1472. 6. Azziz R G~y F Thc tn-~tme-nc ofhyperandwi;rc11isi1) wiLl1 t,ral comraceptivcs. &min Re[m•l F,lucrin,il 1969;7:246-l 54 7. Murphy A, Cropp CS, Smi,h B<;, " a,I Effcct of low-dose or::1 l comrac.eptive on gonadotrCpi1,s1 fmdmgcns, and scx honuom: hinding glnhulin in nonhir.sure womeo

Fcrtil Steril. 1990:53:35,39 8. van der Van1{e N, Dlai,keo:;k in J,,fA, Kl<x)stcrbocr HJ, ct a l. Eff<~cts of seven low,dose co111bim:<l ural contraceptivb on sex hormonc bin ding globulil, corcicoste-roid bindin,:: gk,hulin, total ,md frc.c restosreronc Onuroapáon 1990;41:345-352 9. Jung-H,Jffm,m e, Kuhl 11 Divergem eff~~ of LWO low--doSc mai c.:nntr Aceptivcs on scx-hormone,binditl,~ Pharmaceuck als; 2007. 13. v;m Vlorcn WA, van llaselen CV, van Zuuren EJ, et al The effcct oí 2 comhined <.m•l comracepuves con raining either drospilenone or cyprútt!rom: ~•c;ctatc on acJ1c and scbo« hoa. Curis 2002;69(suppl 4):2,1 5 14. TI1t,mc:)·c:rofr H, Collnick 11, Schellschmidt 1 Supetio1ily of a cumhinel) contr:-tt.:t:pttvc cont~ining drospirenone to a triphasic preparation conrnining norgcsum,Hc ln s•cnc ttc,mucm . Cutis 2004,74123, 130