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OralContraceptives:TheirModeofActionandDermatologic
Applications
MilenaPitashny,MDHelenaMartinezdeMorentin,MDSarahBrenner,MD
Skinmed.20054(2):101104,106.

Introduction
Thefirstcontraceptivepillavailableforhumanusein1960containedtheestrogenmestranol,anethinylestradiolprecursor,ina
veryhighconcentration(150mg),andnorethynodrel,a19nortestosteronederivateprogestin. [1]Thehighdoseofestrogenin
thesepillswasimplicatedinthedevelopmentofcardiovascularandthromboembolicevents,andstartingin1970thedosesof
ethinylestradiolweresignificantlyreduced.Modernpills,knownas"lowdoseoralcontraceptives(OCs),"containethinylestradiolat
concentrationsof2035g.Thesubsequentdiscoveryofdeleteriouseffectsofprogestinonthelipidprofilepromptedaflurryof
researchintoOCsthatledtoanunderstandingofthemechanismofactionofthecombinationofestrogenandprogestin,its
influenceonandrogenicmetabolism,andthedevelopmentofnewsyntheticprogestinstoreplacethe"old"ones.Theseinnovative
OCswerefoundtobesafeinyounghealthywomenwithoutriskfactorsforheartdisease,lipiddisorders,orglucosemetabolism
disorders.
OCshavealsobeenfoundusefulinthetreatmentofseveralgynecologicalanddermatologicaldisorders.Ithasbeenknownfor
yearsthattheinterferenceofOCsinhormonalmetabolismbenefitsacnetreatment,andtodaytheyareanacceptedtreatmentfor
mildtomoderateacneaswellashirsutisminhealthywomen.
Itiswellknownthatandrogensinthepilosebaceousunitpromoteskinproblemssuchasacne,seborrhea,hirsutism,and
androgeneticalopecia(AGA)().Androgenreceptorsarelocalizedinthebasallayerofthesebaceousglandandinkeratinocytesof
theoutersheathofthehairfollicle.Androgensthatinteractwiththesereceptorsaremainlytestosteroneanddihydrotestosterone
thelatteris510timesmorepotentthantheformer.
HormonesinOralContraceptivesandTheirImpactontheSkin

Acne
Androgensstimulatetheproliferationanddifferentiationofsebaceousglandsandsebumsecretion,andpromotefollicular
hyperkeratinizationinacne.Insevereacne,elevatedserumandrogenscanbemeasured.Inhyperandrogenicstates,suchas
polycysticovarysyndrome,thereisahighincidenceofsevereacne.Incontrast,themajorityofwomenwithmildtomoderateacne
havenormalandrogenlevels.Twoexplanationsforthepresenceofacnewithoutandrogenserumexcesswereproposed:1)alocal
excessinandrogenproductionoralteredlocalmetabolismand2)astateofhypersensitivitytocirculatingandrogensduetoan
increasednumberofreceptorsoranabnormalpostbindingresponse. [2]

Hirsutism
Hirsutismisknowntobepresentinwelldefinedandrogeneticareas,andlikeacne,appearsinhyperandrogenicstates,requiring
furtherinvestigationhowever,5%10%ofhirsutewomenhavenormalserumandrogenlevels.Thisidiopathichirsutismiscaused
byincreasedsensitivityofthepilosebaceousunittonormalcirculatingandrogenlevels. [3]

AGA
TheroleofandrogensinthepathophysiologyofAGAhasbecomeclearinrecentyearswiththediscoveryoftype25reductase
inpapillacellsofthehairfollicles.Thisenzymetransformstestosteroneintodihydrotestosterone,particularlyinareasofthescalp
affectedbyAGA.Iftherearesignsofhyperandrogenism,anendocrinologicevaluationisindicated.Incasesofacneorhirsutism
thatarenotduetoandrogenexcess,OCtherapyshouldbeconsidered.

AntiandrogenicEffectofOralContraceptives

EstrogenandprogesteronecombinedinOCsactinasynergisticmannerinthegonadotropinaxis.Theydecreasethesecretionof
hypophysialluteinizinghormoneandfolliclestimulatinghormonebynegativefeedback,therebyinhibitingovulation.Gonadotropin
inhibitionalsohastheeffectofreducingtheandrogenproductionofovarianthecacellsandadrenalgland.Anadditional
antiandrogeniceffectofestrogenscomesfromtheirstimulationofliverproductionofsexhormonebindingglobulin(SHBG),a
globulinthatbindsfreecirculatingandrogensandreducesfreeavailabletestosteronetoperipheraltissues.Highdosesofestrogens
maydecreasesebumproduction,butapparentlygreaterdosesthanthoseinOCarerequiredforsuchaneffect. [2]
Theroleofprogestinsinandrogenmetabolismiscomplex.Syntheticprogestinsderivedfromtestosterone(19nortestosterone
derivatives)orprogesterone(19norprogesteroneor17OHprogesteronederivatives)notonlybindtotheprogesteronereceptor,
theyalsohavetheabilitytobindothersteroidreceptors.Theseincludeandrogenreceptorshavingandrogenicorantiandrogenic
effects,estrogenreceptor,andglucocorticoidreceptorandmineralocorticoidreceptor,whichinterferewithwatermetabolism.Most
OCscontaintestosteronederivedprogestins,withtheexceptionofdrospirenone,whichisanewprogestinderivedfrom17
spirolactonewithpharmacologyresemblingthatofendogenousprogesterone. [2,4,5]Theseprogestincompoundswereproposedto
aggravateacne,hirsutism,orAGAbyincreasedintrinsicandrogeniceffect.
Whenstudiedseparatelyfromestrogen,thedifferentprogestincompoundshavevariableandrogeniceffectbytheirlinkagewiththe
androgenicreceptor.Ontheotherhand,progestinscounterthebeneficialestrogeneffectonSHBGbyreducingthisbindingprotein
inserum,thusbeing"antiestrogenic"andandrogenic.Althoughsomeprogestinshavemoreandrogeniceffectthanothers,when
combinedwithestrogenstheysynergisticallydepressthegonadotropinsecretion,decreasingandrogensecretion.Thecounteraction
ofestrogensandprogesteroneinSHBGresultsintheenhancementofthisbindingprotein,withanetreductioninfreeavailable
androgen.Thus,regardlessofthetypeofprogestininvolvedincombinedformulations,allOCsareantiandrogenic. [2]
Evennorethindrone,afirstgenerationprogestinknowntohaveamarkedintrinsicandrogeniceffect,hastheneteffectof
enhancingSHBGwhengiveninproperdosesandincombinationwithlowdoseethinylestradiol,resultinginreductionoffree
testosterone.Furtherstudiesareneededtoassesstheandrogenicskinendpointeffects. [6]
TheclassificationofOCprogestinsintheliteratureisconfusing.Generationsarenotstandardized,andonecompoundmayappear
indifferentgroups.MostoftheavailableOCscontainderivativesof19nortestosterone,whichmaybeclassifiedintotwofamilies:
estraneandgonane.Theestranegroup(firstgenerationOC)iscomposedofnorethindroneandotherprogestinsthatmetabolizeto
norethindrone(includingnorethynodrel,theprogestincomponentofthefirstpill).Thegonanegroupissubdividedintotwogroups:
Norgestrel,oritsbiologicallyactivederivate,levonorgestrel,knownassecondgenerationOC,derivatefromnorethindrone,and
havevaryingdegreesofandrogenic,estrogenic,andantiestrogenicactivitiesandthe"new"gonanes(orthirdgeneration)
desogestrel,gestodene,andnorgestimatewhicharereportedtohavetheleastandrogenicintrinsicactivityoftheprogestin
compounds. [1]
Newprogestinshavebeensynthesizedinthepastdecadewithnointrinsicandrogeniceffectsbutpotentantiandrogenicactivity,
includingcyproteroneacetate,chlormadinoneacetate,anddienogest.Theirantiandrogenicactivityisinducedbyblockingthe
androgenreceptorsintheskintargetandbyreducingtheactivityof5reductaseinsebaceousglandandhairfollicles.
Cyproteroneacetateandchlormadinoneacetatealsohavepotentantigonadotrophinactivity,which,asnotedabove,reduces
ovarianandadrenalandrogenproduction. [7]Dienogestslightlyaffectsthegonadotrophicsecretionitsinhibitionofovulationis
mainlyduetoitsactivityintheperipheraltissues,reducingserumprogesteronetoanovulatorylevels. [8]CombinationOCs
containingthisgroupofantiandrogenicprogestinshavebeenshowntoimproveseborrhea,acne,hirsutism,andandrogenrelated
alopecia.
Anotherprogestinisdrospirenone,derivedfrom17spirolactoneandpharmacologicallyresemblingendogenousprogesterone.It
hasbothantiandrogenicandantimineralocorticoidactivities.Itisantiandrogenicbyinhibitingovarianandrogenproductionlikeother
progestins,anditalsoblocksandrogenreceptorsintheskin.
Estrogenstimulatesangiotensinsynthesisandenhancesaldosteronemediatedwaterandsodiumretention,makingitresponsible
forsuchunpleasantsymptomsasbloating,breasttenderness,andweightgain.
Drospirenonecountersestrogeneffectbyblockingthealdosteronereceptor,thusbeingantimineralocorticoid.Thisuniqueprogestin
attenuatestheaforementionedbothersomeestrogeniceffectsthatsomewomenreportwiththeuseofOC.Itisalsoreportedto
improveandrogenrelatedskindisorders,includingacne,hirsutism,andseborrhea. [5]

OralContraceptivesandAntibiotics

Theeffectofantibioticsonoralcontraceptivesisonlytheoretical:theactionofbroadspectrumantibiotics,whichreducethegut
florabacteria,mayresultindecreasedabsorptionofestrogen.Thefewstudiesintheliteratureaboutpregnanciesassociatedwith
theuseofantibioticstogetherwithOCsreportedanonsignificanthigherrateofpregnancies/100womanyears. [9]

TheOptimalOCWithRegardtoDermatologicConsiderations
Studiesdemonstratethatacombinationofantiandrogenicprogestins(cyproteroneacetate,chlormadinoneacetate,anddienogest)
[10,11]ordrospirenone[12,13]withethinylestradiolismorebeneficialthanothercombinationOCsforwomenwithapreexisting
androgenrelateddisorder,includingmoderatetosevereacne,seborrhea,mildtomoderateidiopathichirsutism(drospirenonehas
lesseffectonhirsutismthantheantiandrogenicprogestins),andandrogeneticalopecia.Womenwhocomplainaboutwater
retentionsecondarytotheuseofcombinedOCsshouldswitchtoadrospirenonecontainingOC,proventocounterthiseffect.
Drospirenoneisalsobeneficialforskinandrogenrelatedconditionshowever,patientswithrenalfailure,hepaticinsufficiency,and
adrenalinsufficiencyshouldavoiddrospirenonecontainingOCsbecausetheprogestin'santimineralocorticoideffectmayleadto
hyperkalemia.
Indeed,thechoiceoftheoptimalOCmusttakeintoaccountthepatient'sdermatologicalcomplaints(acne,hirsutism),health
history(obesity,deepveinthrombosis,cardiovascularhistory,ovarianandbreastcancer,migraine),age,andhabits(smoking).As
withanyotherdrug,therearecontraindicationstooralcontraceptives:smokersovertheageof35,historyofthromboembolism,
cerebrovasculardisease,coronarydisease,uncontrolledhypertension,hepaticfailure,abnormalvaginalbleedingofunknowncause,
focalmigraine,andsuspectedorknownbreastcancer.
AdverseeffectsofcombinedOCsonhealthywomenareminimalandnonspecific(nausea,vomiting,headache,breasttenderness,
depression,nervousness),andtheirincidencedeclinesovertime,butitshouldberememberedthatpatientswithamedicalhistory
ofthromboemboliceventand/orriskfactorsforcoronarydiseasearepronetodevelopmorelifethreateningadverseeffectsofOCs.
References

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ReprintAddress
SarahBrenner,MD,DepartmentofDermatology,TelAvivSouraskyMedicalCenter,6WeizmannStreet,TelAviv64239Israel.E
mail:derma@tasmc.health.gov.il.
Skinmed.20054(2):101104,106.2005LeJacqCommunications,Inc.
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