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FOGSI FOCUS

PROGESTERONE THE FEEL GOOD

Editor : DR. ASWATH KUMAR R

Sub Editor : DR. NILESH UNMESH BALKAWADE 2 FOGSI FOCUS FOGSI FOCUS The FederationofObstetricandGynecologicalSocietyIndia Jacob Circle,MahalaxmiEast, THE FEEL GOODHORMONE Ph: 32954564/2302164823021654 /23021343 Model Residency, 605,BapuraoJagtapMarg, Dr. NileshUnmeshBalkawade Email: [email protected] Dr. Aswath Kumar Raghu Kumar Dr. Aswath Year ofPublication2014 Design Published by :smritidesign.in Editors Title: Mumbai 400011, India (FOGSI) team forworkinghardtobringforththiswonderfulfocus ! patients . and itsnumerousapplicationswhicheventuallybenefitour us acquaintedwiththearmamentariumofvariousprogesterones form. SothisFOGSIFOCUSrefreshesourknowledgeandgets where wehavetouseprogesteronederivativesinoneortheother or carry. word isderivedfromtheLatinword-‘Gestare’meaningtobear hormoneresponsibleformaintenanceofpregnancy. The latest information. FOGSI FOCUSthisyeartoempowerourfraternitywiththe India -PledgeforExcellence’ HORMONE FOGSI FOCUS I wishtocongratulateDr. Ashwath Kumarandhisentire In ourdaytoobstetricpracticewecomeacrosssituations Progesterone isconsideredtobethemostimportantnatural We havecarefullychosensomeimportantsubjectsforour Mythemeforthisyearis- It isindeedagreatpleasuretowritethismessageforthe Dear FellowFOGSIANS ’.

There isnosubstitute for hardwork. on‘PROGESTERONE THE FEEL GOOD . ‘ Thomas A. Edison Empower WomenEmpower

Dr. SuchitraN.Pandit President FOGSI2014

3 FOGSI FOCUS

From Editors Desk

Dear colleagues, It gives me great pleasure to bring to you this FOGSI Focus on Progesterone. Progesterone is the ‘feel good’ factor amongst dominated environment. Situations like PCOD,DUB, are so DR. NILESH UNMESH DR. ASWATH common these days. Majority are due to estrogen dominance and BALKAWADE KUMAR R altered Estrogen:Progesterone ratio. Answer to these and many other common and rare problems lies in the feel good effect of Progesterone. Its a boon for common problems like PCOD, Obstetric problems like defect to some rare diseases such as neuro degeneration on which research is going on. It has played a major role in advanced fields like IVF. New uses like that in preterm labor, are being tried with variable success rate. But this doesn’t impede Research in this important yet enigmatic molecule called Progesterone. Our president, Dr SuchitraPandit has really helped and encouraged us in making of this FOGSI Focus.I thank all our contributors who despite of their busy schedules have taken time to write these articles. This FOGSI Focus would not have been possible with outthe support of INTAS pharmaceuticals, and we are really grateful to them for their wholehearted support. I hope this FOGSI Focus on Progesterone will bring to you all the updated knowledge and information that you seek and go a long way in your practice. Thanks Editors 6 FOGSI FOCUS FOGSI Office Bearers2014-2015 Dr. GokulChandra Das Vice President Dr. SheelaMane Vice President Dr. Jaydeep Tank Treasurer Dr. Prakash Trivedi President Elect(2015) Dr. RozaOlyai Vice President Dr. IndraniGanguli Vice President Dr. SuchitraPandit President Dr. NozerSheriar Secretary General Dr GorakhMandrupkar Jt. Secretary Dr. RituJoshi Vice President Dr. MadhuriPatel Jt. Treasurer Dr. HrishikeshD.Pai Deputy SecretaryGeneral Dr. HemaDivakar Immediate PastPresident hpe RGSEOEI P 51 47 PROGESTERONE Chapter 9 39 35 PROGESTERONEINRPL Chapter 8 LUTEALPHASE DEFECT Chapter 7 PROGESTERONE– ANSWER TO ESTROGEN DOMINANCE 27 Chapter 6 23 PROGESTERONECAFETERIAINCONTRACEPTION Chapter 5 SAFEMOTHERHOOD:PROGESTERONEROLEINOBSTETRICS 4 Chapter 13 09 RAINBOW:NATURAL PROGESTERONE TOSYNTHETIC Chapter 3 PATH THROUGH THE BODY- &PHARMACOLOGY 2 Chapter HISTORY OFPROGESTERONE: THE ‘FEEL-GOOD’ HORMONE Chapter 1 Index Author: DURING INVITROFERTILIZATION (IVF)CYCLES Authors: Dr.Ajay Mane,Dr.Rajendrasing Pardeshi Authors:Dr.Alok Sharma, Dr.Sandeep SinghRathore Authors: Dr. Manjula Anagani, Dr. Anitha Nelakuditi Authors :Dr. SuchitraN.Pandit ,Dr. SwatiBhargav Authors: Authors: Dr. GorakhMandrupkar, Dr. RDShriwastav Authors :DrJyothika A Desai,DrShailajaN Authors: Dr Aswath KumarRaghu,Dr. NileshUnmeshBalkawade

Dr FessyLouis T

Dr.Neetha George UPEETTO 55 SUPPLEMENTATION , Dr.Elavarasi Elamaran

7 FOGSI FOCUS 8 FOGSI FOCUS hpe 2POETRN I EOASLTEAY71 78 67 75 61 NEWRESEARCHONPROGRESTERONE AND ITSMETABOLITES 14 Chapter PROGESTERONE:DIFFERENT DRUGDELIVERY SYSTEMS Chapter 13 PROGESTERONEINMENOPAUSAL THERAPY 12 Chapter ROLEOFPROGESTERONEINCANCERS 11 Chapter PROGESTINSINENDOMETRIOSIS Chapter 10 Author: DR.NAZIA ISHRAT, Author: Dr. SaieG.Mandrupkar, Dr Authors: Dr. Abha RaniSinha,Dr. SushmaSingh Author: Dr.Sebanti Goswami Authors: DrPratik Tambe MDFICOG, DrLataRajputMD

PROF. SEEMA HAKIM Sonali Bichkar things. of theevolutionandfunction ofprogesteroneinliving The newdiscoverymaychange scientificunderstanding ago, beforetheappearanceof modernplantsandanimals. an ancientbio-regulatorthat evolvedbillionsofyears origins hasbeenpushedback. progesterone moleculesinthewalnuttree,dateof its existence. However, withthediscovery, in2010,of which isgenerallyacceptedasthetimeframeof its repair. neuroregeneration, repairofbraindamageandmyelin progestin Nestoronea(®)havepositiveeffects on in animalexperimentsthatprogesteroneandthe tree andasnewtheongoingresearchwhichhasshown —Samuel Johnson pity oneitherside” of theoldandyoungendsgenerallywithcontemptor appearance naturallyproduces, thattheconversation the opinionsandsentimentswhichthiscontrarietyof to thefuture, orbackward tothepast;andsodifferent “So different are thecolorsoflife, aswelookforward Life ishowwelookatit. The ‘Feel-Good’Hormone History OfProgesterone: Additional ProfessorDeptofGynaecology, Jubulee MissionMedicalCollege, Thrissur The researchersspeculatethatthehormonemightbe The historyofprogesteronespans500millionyears The historyofProgesteroneisasoldthe Walnut DR ASWATH KUMARRAGHU Dip. in Advanced Laproscopy, France Chairperson, FOGSIQuizCommittee 1 MBBS., M.D.,FICOG

2

Excretion renal Terminal half-life 13.181.3 hepatictopregnanediolsand Protein binding96%-99% prolongedabsorption Melting point126C(259F) Synonym 4-pregnene-3,20-dione Molecular weight314.46 30, Oxygen2) Molecular FormulaC21H30O2(Carbon21,Hydrogen Facts aboutprogesterone

Gynaecological Society(POGS) MCM, PuneObstetric& College, Pune Assist. Prof.Dr. D. Y. PatilMedical M.S., D.N.B.,F.I.A.G.E. DR NILESHUNMESHBALKAWADE 1

9 FOGSI FOCUS 10 FOGSI FOCUS , estrogen,cortisoneetc. synthesis of‘progesterone’. , theyareusedasstartingpointsforthe these sterolshaveasimilarmolecularstructureto , hecogenin,,solasodine. As . some solanumspecies,maizeandmanymorecontain yams, fenugreek,sisal,calabarbean,somelilies,, including humans. point forthesteroidhormonesmadenaturallyinanimals, which isfoundinanimals.Cholesterolthestarting Facts aboutplantsterols recounted thediscoveryand isolationin1974anarticle isolated andlaternamed progesterone. Willard Allen be confusedwithprogestin, asyntheticprogestogen i.e., asubstancewhichfavorsgestation.” reason wewishtopropose foritthename to aidgestationinthecastratedrabbit;andforthis action liesinitsability, byalterationoftheendometrium, acquainted withitsphysiologicalbehavior, itschief characteristic effectsintherabbit.Insofarasweare as ahormonewhichinducestheabove-described this hormoneofthecorpusluteum,referring toitonly ...We haveasyetproposed nonamefor known byprevious experimentationtobeduethe , characteristicofearlypregnancy, and special histologicalandphysiologicalstateofthe recently spayedfemalerabbits,regularly bringabouta corpus luteum.Theseextracts,wheninjectedinto described thepreparation andeffectsofextractsthe Modern historyofprogesterone the corpusluteum. published thefirstpaperonextractingprogesteronefrom substance inthecorpuslutuemthatsustainedpregnancy embryology laboratorythatthetwodiscovereda It waswhileworkinginProfessorGeorge Corners trained firstasanorganic chemist,thenstudiedmedicine. discovery andisolationby Progesterone isthenfurthersynthesisedinto Some ofwhicharestigmasterol,,sitosterol, suchasthesoybean,Dioscoreaspeciesof Phytosterols aremolecularlysimilartocholesterol It wasn’t until1933thatthepurehormone was Progestin, theoriginalname ofprogesteroneshouldn’t “In previous papersofthepresent serieswehave On September23rd,1929 Willard Allen PhD, The modernhistoryofprogesteronebeginswithits 3 Professor Willard Allen : progestin who , Willard Allen abouttheirindependentdiscovery. progesterone fromthecorpus luteum,correspondingwith cholesterol. In1934he isolated asmallsampleof between themolecularstructures ofandrosteroneand oestriol. In1933heshowed for thefirsttimesimilarity time, heconfirmedtheexistenceofanotherestrogen, independently in America, alsodiscoveredoestrone. collectively asestrogen.EdwardDoisy, working isolated oestrone,oneofagroupsteroidsknown . testosterone. And totheadrenalhormonescortisoland by theadrenalglands,brainandglialcells. the testesinmales,whilesmalleramountsareproduced the lutealphase). differences betweenmenandwomen(atleastoutside testosterone inmales. There arenogreatquantitative . These aregovernedbyestrogeninfemalesand secondary sexualcharacteristicswhichdevelopat been largely overlooked. but a‘sex’ hormonetoo.Soit’s manyotherroleshave come toberegardedasanotonly‘female’hormone, entitled. RecollectionsofmyLifewithProgesterone was sittingontopoftheworld. born. MyfriendsgavemedoublecongratulationsandI luteum hormone.OnMay18,mydaughter, Lucille,was glorious month.OnMay5,Ihadthecrystallinecorpus experience. However, themonthofMay1933wasa vacuum distillationwasalaboriousandexasperating hormone from thewaxymaterialobtainedbyhigh- In 1931Butenandtisolatedandrosterone. At thesame In 1929 Adolf ButenandtPhD,working inGermany, It istheprecursortosexhormonesestrogenand It issecretedprimarilybytheovariesinfemalesand It isnotasexhormone;itplaysnopartinthe In hindsightitwasanunfortunatename,asit’s now pure Willard M. Allen. remarkable discoverer, been writtenaboutits progesterone. Butlittlehas changing, femalehormone been devotedtotheworld- life. very significantdayinhis by him The day Allen isolated Considerable spacehas “...... ” progestin progesterone The isolationofthe 4 (laternamed ) wasa ‘ using atechniquewhichhassincebecomeknownasthe sarsparilla ,couldbeconvertedintoprogesterone By 1937hehadconvertedthistoprogesterone. fromanextractofpregnantmare’s . The EraofMarkerDegradation: progesterone from soybeanoil.By1940hewasableindoing production ofcortisone.In1939heisolatedstigmasterol fromplantsterols.Hisworklaterleadtothe known forhisworkintheindustrialsynthesisofhuman 130 patents,andmanyhonorarydegrees.Butheisbest Percy Julianwasaremarkablechemistandawarded (Physostigma venenosum),fromwhichthenamederives. for producingprogesterone. in thisPennState lab,searchingforsynthetic methods ’ In 1938hefoundthesterolsarsasapogenin,from In 1936 Russell Markerspentmuchofthe1930sand1940s production. Russell Marker the West African calabarbean PhD extractedstigmasterolfrom Prize forChemistryin1939. . had synthesizedtestosteronefrom who wasworkingindependently, Butenandt andLeopoldRuzicka, testes. Shortlyafterthisboth isolated testosteronefromthe . 5 At thesametime,PercyJulian They wereawardedtheNobel By 1935ErnstLaqueurhad isolatedthesteroid bulk Schering intheU.S.1945as early 1960s. Novum contraceptives ( in someofthefirstoral and wasusedastheprogestin the U.S.in1957as marketed byParke-Davisin inMexicoCity, was Djerassi, LuisMiramontes,andGeorge Rosenkranzat nor analogofethisterone,synthesizedin1951byCarl (norethindrone, 19-nor-17á-ethynyltestosterone), the19- Skokie, Illinoisandused as theprogestinin synthesized in1952byFrank B.ColtonatSearlein The Pill: was marketedinGermany1939as Hohlweg and Arthur SeriniatSchering AG inBerlin, by HansHerloff Inhoffen, Willy Logemann, Walter rearrangement ofthe5,6doublebondto4,5position, or afteroxidationofthe3-OHgrouptoketone,with byaddingacetyleneeitherbefore ethynyl analogoftestosterone,synthesizedin1938from (pregneninolone, 17á-ethynyltestosterone),the17á- progesterone. Syntex became thepreferredprecursortocortisone.In1951, control. to getinvolvedinwasthecontroversialareaofbirth — oranyoftheothermajordrugcompanieswanted response wasno.Intheearly1950s,lastthingSearle research foranoralcontraceptive,Searle’s immediate pharmaceutical companyG. D.Searle aboutfunding ‘ partners, acompanywhichcompetedwithPercyJulian’s progesterone in1943. converted thediosgeninintothreekilogramsof But againundeterred,heborrowedafriend’s laband pharmaceutical companywasinterestedinhisdiscovery. the Dioscoreaspeciesofa searched forandfoundin1941,thesteroldiosgenin soybean progesterone’ A morepotent Norethynodrel, anisomer ofnorethisterone,was The firstorallyactiveprogestin, Marker’s progesterone,becauseofitslowcost,later When scientistGregoryPincusfirstapproachedthe In 1944heformedSyntexinMexicoCitywithtwo This couldalsobeconvertedintoprogesterone.No But sarsparillawasexpensive,soundeterred,he haddevelopedthe , Norinyl 6,7,8,9,10. , etc.)inthe orally active Norlutin Ortho- . first oralcontraceptive , growingwildinMexico. progestin, Pranone Proluton C . 6,7,8,9. Enovid andby from ,

11 FOGSI FOCUS 12 FOGSI FOCUS conducted inPuertoRicotoavoidUS-FDA norms. rebound’. The researchbyRockandPincuswas vigorously andenablehispatientstoconceive.—‘Rock that thereproductiveorgans would“rebound”more . Then, afterstoppingtreatment,hishopewas that thedrugwouldallowtheirbodiesto“rest”from progesterone onhisinfertilefemalepatients.Hetheorized his utterastonishment,Rockwasalreadytesting Pincus ranintoanoldacquaintance,Dr. JohnRock. To (FDA). At amedicalconferenceintheearly1950s, approval bytheU.S.FoodandDrug Administration Searle’s bestsellingproductforyears. company initiallywantedproduce,turnedouttobe contraceptive thatno from Pillsales. The Pill,the $24 millioninnetprofits In 1964alone,Searletookin contraceptive in1960. and approvedasthefirstoral marketed intheU.S.1957 mankind andwillbesoin the future the newermoleculesofsteroidshasbeenaboonto involved invariousresearchprojects,theinvention of currently undergoing clinicaltrials. Fourth:,,nestorone, · Third():,, · Second(gonane): , norethisterone, · First():norethindrone,norethynodrel, · Progestins thenfurthercameupwithfollowingclasses: acetateandtrimegestone , drospirenone norethindrone acetate,ethynodioldiacetate Although historyshowsthatsomeethicalissueswere isanon-steroidal progestinwhichis After alotofresistance,thepillcameintomarket 6,7,8,9,10. human trialsnecessaryfor would bethelarge-scale hardest partsoftheprocess pill, heknewoneofthe come upwithabirthcontrol asked GregoryPincusto advocate Margaret Sanger When birthcontrol 11 1 http://www.pbs.org/wgbh/amex/pill 11. DjerassiC(2006).“Chemicalbirthofthepill”. 9. Sneader, Walter (2005).“Hormoneanalogues”. 8. Petrow V (1970).“Thecontraceptiveprogestagens”. 7. Maisel, Albert Q.(1965). 6. 10.Djerassi C,MiramontesL,RosenkranzG, Marker, RussellE.;Rohrmann,Ewald(1939), 5. W. M. Allen, “Mylifewithprogesterone”, 4. W.M. Allen, “Physiologyofthecorpusluteum, V: 3. GuidoF. Pauli,J.BrentFriesen, Tanja Gödecke, 2. Sitruk-Ware R,El-EtrM.Progesteroneandrelated 1. References: 4089–91. doi:10.1021/ja01645a009. Sons. pp. 188–225. ISBN 0-471-89980-1. discovery: ahistory cr60268a004. PMID 4098492. Chem Rev York:543168. RandomHouse.OCLC 3592 ” (PDF). 19-Nor-17á-ethynyltestosterone and19-Nor-17á- Sondheimer F(1954).“Steroids. LIV. Synthesisof j.ajog.2005.06.010. PMID 16389046. Obstet Gynecol Pregnanediol-3(á),20(á)”, “Sterols. LXXXI.ConversionofSarsasapogeninto 1577. Obstetrics &Gynecology 92 (1930),pp.174–188. produces progestationalproliferation”, progestin, ahormoneofthecorpusluteumwhich the preparationandsomechemicalpropertiesof J. Nat.Prod. Norman R.FarnsworthandBernhardGlodny May 29. doi: 10.3109/13697137.2013.802556.Epub2013 2013 Aug; 16Suppl1:69-78. progestins: potentialnewhealthbenefits.Climacteric.

, 2010,73(3),pp338–34 70 (6):713–26.doi:10.1021/

194 . Hoboken,NJ:John Wiley & (1):290–8.doi:10.1016/ The HormoneQuest , 193(4)2005,pp.1575- J. Am. Chem.Soc. J Am ChemSoc Am JPhysiol

76 61 . New Am J (16): (12): Drug Am J

species. andembryogenesisofhumansother steroid hormoneinvolvedinthefemalemenstrualcycle, or morecommonly, thepregnancyhormone,isaC-21 Progesterone alsoknownasP4(pregn-4-ene-3,20-dione) on theirintroductioninthemarket Prostesterones areclassifiedbasedontheirstructureand Classification: PHYSIOLOGY &PHARMACOLOGY PATHBODY- THROUGHTHE

Bangalore SocietyofObstetrics Dr Jyothika A Desai Imm. PastPresident and

PESIMSR, Kuppam– A.P. Associate ProfessorofOBG Dr ShailajaN 2

13 FOGSI FOCUS 14 FOGSI FOCUS which increaseclinicalpregnancyrates. decreasing harmful Th 1cellsandincreasing Th 2cells progesterone inducedblockingfactor(PIBF),thereby withdrawal bleeding. to prolongedaxissuppressionitisnotidealfor asynchrony. Itisidealforendometrialprotection.Due as thenaturalcompoundwithlesserendometrial,stromal : Micronized progesterone effects. the mineralocorticoidreceptorwithanti- an analogueofSpironolactone.Ithasahighaffinity for ovulatory agents Norgestimate- theyarelipidfriendly&potentanti- activity makethemeffective contraceptives. action onpituitarygonadotrophinsandhemostatic levonorgestrel, d-norgestrel: Their stronginhibitory norethynodrel andGonane(IIndGeneration)- secretionwithoutandrogenicactivity. potent progestationalandanti-androgenactivity -Itinducesproductionof acetate–Ithasasimilaraction IVth Generation IIIrd Generation Estrane (IstGeneration) - Itisastronginhibitorof Acetate– Itisaderivativeof17OHP with Advantages : Adrenal andrenalfunctionsareunaffected clotting factorsandlipoproteins It hasnoadverseeffect onB.P, weight,blood Being adiureticitpreventssodiumretention empty . at nightassedationisasideeffect) isrequired. divided doses(mostly100mgbyday&200mg can beachieved bioavalability) particle sizeincreasesabsorption& friendly. Short actingandneedsmultiple doses Maximum absorptionafterfoodthanonan To fullyprotectendometrium-300mg/dayin Dose dependentincreaseofserumprogesterone It isanaturalprogesterone(decreasingthe : Drospirenone–aprogestinthatis : Desogestrel,Gestodene, : -norethisterone, “rescued” bythepresence ofhumanchorionic produced initiallyfromthe corpusluteumthathasbeen . Progesteroneisalsostoredinadiposetissue. luteum), theadrenalglandsandduringpregnancy, inthe Source branches. Itishydrophobic. oxygenated functionalgroups,aswelltwomethyl interconnected cyclichydrocarbons,ketoneand chain derivedfromcholesterol.Itconsistsoffour Chemistry: In humans,duringpregnancy, progesteroneis Progesterone isproducedintheovaries(bycorpus Progesterone isacompoundwith21carbonatom : : challenge test premenstrual syndromeandforprogesterone cardioprotective) Suitable fortreatmentofLPD,DUB,HRT, Favours diuresis(sousefulinHRT as : Synthesis: like in Plant: bioavailable progesteronegoesup. After consumptionofmilkproducts,thelevel week, productionofprogesteroneshiftstotheplacenta. (hCG)fromtheconceptus. After the8th progestin/gestagen. the lab.Syntheticprogesteroneiscalledprogestogen/ progesterone availableinthemarketissynthesized “natural progesterone”isreallyamisnomersinceall will notboostone’s progesteronelevels. The term progesterone fromdiosgenin,soeatingwildyamorsoy from thisdiosgenin.Thehumanbodyisnotabletomake Dioscorea polygonoides odcnrcpiePMSlikesymptoms Decreases HDL Good contraceptive Good haemostat Fluidretention Androgenicilleffects Good oralabsorption Disadvantages inactivation hepatic metabolism, rapid Bypasses firstpass Advantages Dioscorea Progesterone-like steroidcalleddiosgeninisfound An additionalsourceofprogesteroneismilkproducts. species oftheyamfamily(nativetoMexico) mexicana . Progesteronecanbeproduced native progesterone the biologicalbenefitsof Not abletoconveymanyof , Dioscorea villosa and synthesized byyeast. converted totestosterone,estroneandestradiol. andandrostenedione. canbe hydroxyprogesterone (anothernaturalprogestogen)of aldosterone, andafterconversionto17- right) istheprecursorofmineralocorticoid isomerase. hydroxysteroid dehydrogenase/delta(5)-delta(4) reaction. This reactioniscatalyzedby3beta- C-4, fromC-5throughaketo/enoltautomerization keto group(4)andsecond,thedoublebondismovedto in twosteps.First,the3-hydroxylgroupisoxidizedtoa conversion ofpregnenolonetoprogesteronetakesplace This reactioniscatalyzedbycytochromeP450scc. The starting atpositionC-22toproducepregnenolone(3). diol isthenfurtheroxidizedwithlossofthesidechain produce 20,22-dihydroxycholesterol(2). This vicinal androstenedione forsexsteroids. hydroxyprogesterone isforcortisol(),and (mineralocorticoid) synthesis,as17- (3) toprogesterone(6). andprogesteronecanalsobe Progesterone inturn(seelowerhalfoffiguretothe Cholesterol (1)undergoes doubleoxidationto Bottom: Progesteroneisimportantforaldosterone Top: Conversionofcholesterol(1)intopregnenolone

15 FOGSI FOCUS 16 FOGSI FOCUS phase, asshowninthediagrambelow. Progesterone rise afterovulation,andareelevatedduringtheluteal during thepreovulatoryphaseofmenstrualcycle, Levels : performed thetests. provided bythelaboratorythat interpreted usingthereferenceranges follicular phaseofthemenstrualcycle. similar tothoseinwomenduringthe women. Adult maleshavelevels low inchildrenandpostmenopausal In women,progesteronelevelsarerelativelylow Blood testresultsshouldalwaysbe Progesterone levelsarerelatively 100-200 ng/ml atterm. 100-200 progesterone levelsstarttorisefurtherandmayreach ml afterovulation. After theluteal-placentalshift, ng/ ng/ml prior toovulationand>5 levels tendtobe<2 oehnrn 8hrs 12hrs 16hrs Norethindrone Desogestrel 2-3days Gestodene 4-5hrs LNG T1/2 Dydrogesterone DMPA Preparations 12-18hrs Theprogesteronereceptorisinducedbyestrogensat · The Progesterone : Inaddition,progesteroneisahighlypotentantagonist · Themechanismincludes: (1)steroidhormone · Progesteroneexertsitsprimaryactionthroughthe · Physiological mechanisms: sodium-retaining activityofaldosterone. of themineralocorticoidreceptor(MR).Itreduces specific cellularactivity. (6) proteinsynthesisinthecytoplasmthatresults transport ofthemRNA totheribosomes,andfinally, (4) synthesisofmessengerRNA(mRNA),(5) of ahormone-receptorcomplexwithnuclearDNA, hormone bindingtoreceptorprotein,(3)interaction diffusion acrossthecellmembrane,(2)steroid postulated. membrane boundprogesteronereceptorhasalsobeen intracellular progesteronereceptoralthoughadistinct, structure thatallowshormone bindingandreceptor important forfoldingof thepolypeptideintoa is associatedwithadditional proteins,whichare complex systemoftranscriptionregulation.Eachform transcription fromdistinctlydifferent promoters,ina by asinglegene;thetwoformsareconsequenceof the A andBreceptors. The twoformsareexpressed )hastwomajorforms,designated (inafashionsimilartothe (probably throughreceptorphosphorylation). The at boththetranscriptionalandtranslationallevels the transcriptionallevelanddecreasedbyprogestin effects, Androgenic effects andGeneraleffects havedifferent effects:Progestational expression ofprogesteronereceptors.Different Estrogen, throughestrogenreceptorsupregulatesthe that areamplifiedinthepresenceofestrogen. Progesterone hasanumberofphysiologicaleffects Effects On theprogesteronereceptor, TAF-1 islocatedina91- as androgenicapillcontaining1mg ofNE For androgenicity, itwouldbe0.15X3.4=.51orhalf compared toNEwouldbe 0.15X9.0=1.35times. usual OCdoseis0.15mg. Itsprogestinpotency DSG isaverypotentandandrogenicprogestinbutits a larger doseofalesspotentprogestin.Forexample, used inamuchsmallerdoseandthusbeequivalentto effect. However, ahigherpotencyprogestinmaybe per mg,intermsofprogesteroneeffect orandrogen selectivity. Eachprogestinhasadifferent , mg control pillistoachieveahighlevelofprogestational effects areminimized. Typically, thegoalofabirth progestational effects aremaximizedandandrogenic Progestational selectivity: The degreestowhich related sideeffects whichmainlyincludeacneand activity increasethechancesofunpleasantandrogen- Androgenic Effects: Progestinswithhigherandrogenic ovulation andtolessenmenstrualbleeding). progesterone receptors(therebyhelpingtoprevent Progestational Effects: Refer tostimulationofthe that allowstheinhibitoryactionstobemaintained. progesterone antagonistproducesastructuralchange the carboxytailofreceptor. Bindingwitha that overcomestheinherentinhibitoryfunctionwithin Progesterone agonistsinduceaconformationalchange receptor exertsaninhibitoryeffect ontranscription. binding, theC-terminalregionofprogesterone with theother TAFs. Intheabsenceofhormone autonomously activatetranscriptionoritcansynergize contains athirdactivationdomain, TAF-3, and can of TAF-1 alone.Inappropriatecells,therefore,BUS higher thanthatwiththe A receptor, thusbeyondthat to full-lengthhormone-activatedBreceptors,and domain activatestranscriptiontolevelscomparable domain. A fragmentmissingthehormone-binding domain. TAF-2 islocatedinthehormone-binding amino acidsegmentjustupstreamoftheDNA-binding 114,000, with933aminoacids,164morethan A. activity. The molecularweightof A is94,000andB,

17 FOGSI FOCUS 18 FOGSI FOCUS Selectivity Index Some Progestational Compoundsandtheir Biological Activities -ogsrl-++-+ + ------+ - - + + - + - - - -/+ + + + ------/+ -/+ - + - - - L-Norgestrel - + Ethynodiol acetate - Norethindrone Activities + + Norethynodrel Desogestrel - - 19-Nor-testosterone derivatives - + derivatives - derivatives &testosterone -/+ 17 ethinyl-testosterone - acetate Medroxyprogesterone acetate -/+ Hydroxyprogesterone caproate Progesterone Progesterone &derivatives Agent srgncadoei nietoei ninrgncanabolic antiandrogenic anti-estrogenic androgenic Estrogenic Progesterone withaffinitytosteroid Receptor

19 FOGSI FOCUS 20 FOGSI FOCUS Reproductive system: Progesteroneconvertstheendometriumtoits · Thefetus metabolizesplacentalprogesteroneinthe · Adropinprogesteronelevelsispossiblyonestep · Inaddition progesteroneinhibitslactationduring · Progesteronedecreasescontractilityoftheuterine · Duringimplantationandgestation, progesterone · ProgesteronemodulatestheactivityofCatSper · Itcausessuppression ofH-P-O axis,inhibits • to anovulatorydysfunctionaluterinebleeding. develop, levelsofprogesteronemaybelow, leading does notoccurandthecorpusluteum is progesterone-withdrawalbleeding.Ifovulation human, tomenstruation.Normalmenstrualbleeding progesterone levelswilldecrease,leading,inthe impenetrable tosperms.Ifpregnancydoesnotoccur, epithelium andcervicalmucus,makingitthick At thesametimeprogesteroneaffects thevaginal secretory stagetopreparetheuterusforimplantation. toward eggs(chemotaxis). may useprogesteroneasahomingsignaltoswim channels. Sinceeggsreleaseprogesterone, production ofadrenalsteroids. that facilitatestheonsetof labor. delivery isoneofthetriggersformilkproduction. pregnancy. The fallinprogesteronelevelsfollowing smooth muscle. to allowfortheacceptanceofpregnancy. appears todecreasethematernalimmuneresponse (cation channelsofsperm)voltage-gatedCa preovulatory surgeandthereby ovulation. 2+ Itcontrols bleedinginDUB • Itmayaffect gumhealth,increasingriskofgingivitis · Itnormalizesblood clottingandvasculartone, · Itreducesgall-bladderactivity. · Itactsasananti-inflammatoryagentandregulates · Itreducesspasmandrelaxessmoothmuscle.Bronchi · Itincreasesthecoretemperature(thermogenic · Itraisesepidermalgrowthfactor-1 levels,afactor · Other effects Protein metabolism–nosignificanteffect. storage ()andpromotesketogenesis. increases insulinresponsetoglucose,promotesglycogen Carbohydrate metabolism-increasesbasalinsulinlevels, but hasnoeffect onLDL. fat depositionanddecreasesHDL,increasestriglycerides Fat metabolism-stimulateslipoproteinlipase,promotes Metabolic effects: Addiction Effects ofProgesterone onNicotineandCocaine affects regulationofapoptoticgenes. improves memoryandcognitiveability. Progesterone predominantly throughtheGSK-3betapathwaywhich and affect myelination.Itseffect asaneurosteroidworks sterone) affect synapticfunctioning,areneuroprotective, (pregnenoloneanddehydroepiandro- Nervous system Progesteronereducescravingandthefeeling ofbeing · Progesteronereducestheurge tosmokecigarettes, · properties ofthedrug. stimulated bycocainereducingthedopaminergic “bad effects” fromIV nicotineand“drugliking” (gum inflammation)andtoothdecay. of thrombosisinthepredisposed. stores forenergy. Itmaycontributetodevelopment and copperlevels,celloxygenuseoffat immune response.Itincreasesmonocytes. receptors arewidelypresentinsubmucosaltissue) are widenedandmucusregulated.(Progesterone function) duringovulation. cultures ofstemcells. often usedtoinduceproliferation,andsustain Itprovideslocalstromalsupport. Ø Itreducesvascularity &enhancesfibrinolysis. Ø Mechanism ofaction: uterine lining)byregulatingtheeffects ofestrogen. · Itappearstopreventendometrialcancer(involvingthe requiring dailyadministration). via (thoughthe latterhasashorthalf-life or pessaries,transdermally throughagelorcream, can alsobeadministeredas vaginal orrectalsuppositories containing micronisedprogesteroneinoil.Progesterone micronized inoil.Productsareoftensoldascapsules and ispoorlyabsorbedwhentakenorallyunless bioavailability. Progesterone doesnotdissolveinwater progestins havebeendesignedwithimprovedoral of progesteronewhentakenorally, manysynthetic medical applications.Becauseofthepoorbioavailability The useofprogesteroneanditsanalogueshavemany Clinical applications: dimorphic proportionsoftheseorgans certain muscleandfattissuemayhintataroleinsexually sexuality, andthepresenceofprogesteronereceptorsin bone strength,inrespiration,nervetissueandfemale · Progesteronealsohasaroleinskinelasticityand Itstimulatesosteoblasticmediatedboneformation · Byactingontestosteronereceptors,itdecreases · Itcausesalveolobulardevelopmentofthebreast · Itpromotesincreasedadrenocorticalaldosterone · Itcompeteswithaldosteroneattherenaltubules: · Progesteroneplaysanimportantroleinthesignalling · Itinducestheenzymeoestradioldehydrogenase Ø Itinhibitsmitoticactivityoftheendometrialcells Ø Progesteronedecreasessynthesisofoestrogen Ø Itpreventsendogenousovariansteroid Ø Itincreasesthromboxane A2 leadingtoplatelet Ø Itpreventsglandulargrowthbyantagonising Ø SHBG andisresponsibleforacnehirsutism secretory apparatus secretion decreasing sodiumreabsorption affect thesusceptibilitytodiabetesorgestational of insulinreleaseandpancreaticfunction,may estrogen endometrium intoestronewhichisamilder — whichdegradesoestradiolinthe receptors intheendometrium production aggregation. estrogen action. Confucius “Study thepastifyouwoulddefinefuture.”¯ knowledge inthenearfuture. despite theirlimitations,arelikelytoyieldimportantnew which toidentifyprogesterone-regulatedtranscripts, as differential displayPCR andsimilarapproachesby progesterone isurgently required,andtechniquessuch New informationongenesdirectlyregulatedby role inmodulationofprogesteroneaction. and whethertissuelevelsofcoregulatoryproteinsplaya progesterone regulatescoregulatoryproteinexpression needs furtherinvestigationtoclarifywhether The roleofcoregulatoryproteinsinprogesteroneaction the significanceofPR A andPRBexpression. limitation inthisregard.Moreinformationisneededon , andtherelativepaucityofmodelshasbeena the biologyandhormoneresponsivenessofnormal in knowledge. There isagreatdealtobelearnedabout structure andfunctionofPR,therearestillmarkedgaps in themammalianreproductivesystemandmolecular understanding thephysiologicalactionsofprogesterone Although significantprogresshasbeenmadein Future direction:

21 FOGSI FOCUS 22 FOGSI FOCUS MBBS DGOFCPSFICMCHMCSEP(i) PROGESTERONES NATURAL TOSYNTHETIC PROGESTERONE RAINBOW: testosterone andcortisol. precursor toestrogen,itisalsothe of pathway ofhormonalsynthesis.Inadditiontobeingthe ‘Gestare’ meaningto‘bear’ or ‘carry’. in turnproductofcholesterol. declines tolessthan1%ofthepremenopausallevel. , thetotalamountofprogesteroneproduced the cardiovasculartissue,breasttissueandmore. throughout thebodybindingtoreceptorsinbrain, role inmenstrualcycleandpregnancycirculates and ovariesinmenwomenrespectively. Itplaysa adrenal glandsinbothmenandwomen,bythetestes Introduction Progesterone hasseveralbiological actions. Functions ofprogesterone .It bringsaboutthechangesinendometriumwhich 2. Progesterone actsprimarilyasanantagonistto 1. Pristine Women’s Hospital,Kolhapur Consultant, ReproductiveMedicine, Progesterone occupiesanimportantpositioninthe The wordprogesteroneisderivedfromtheLatin Progesterone ismadefrompregnenolone,which It issecretedduringpregnancybytheplacenta.During Progesterone isasteroidhormoneproducedbythe Mandrupkar Clinic,Islampur(ISO enables theimplantationof afertilizedovum. estrogen. Dr. GorakhMandrupkar Joint Secretary, FOGSI 9001:2008) 1

It istruethatthenaturalprogesterone nowavailablehas the plantandisconverted into progesterone. that istakenfrom It containsasteroidcalled‘diosgenin’ family nativetoMexico. in In addition,progesterone-likesteroidsarefound detected. In atleastoneplant, progesterones Classification: NaturalandSynthetic Progestogens therapies (HTs). recent pastforuseascontraceptiveswellhormone endogenous progesterone.) (Progestin: progesteronethatmimicstheactionsof endogenous, naturalaswellthesyntheticsteroids .Itpreventscontractionsoftheuterusandhelpsin 4. Itservestopromotesurvivalanddevelopmentof 3. Naturalprogesterones Several newprogestinshavebeensynthesizedinthe The termprogestagensorprogestogensinclude maintaining pregnancy. embryo andfetus.

2,3 Juglansregia Hospital, Sangli Dept. OBGY, BhartiMedicalCollage& Andheri (W),Mumbai Assistant Prof.SangitaHospital, MD DGO Dr. RDShriwastav . This plantispartoftheyam , progesteronehasbeen 3

23 FOGSI FOCUS 24 FOGSI FOCUS

Improved bioavailability Available inallroutesofadministration. They aresafeinpregnancy. They arewelltolerated. Advantages ofnaturalprogesterones: different assistedreproductivetechniques. prevention ofpretermlabor Mostly usedintreatmentofPCOS,Lutealphasedefects, intramuscular, aswelltopicalroutesareavailable. preparations aresafeandeasytouse.Oral,vaginal, oral preparationsofsame. All thesenaturalmicronized technology hasmadeitpossibletomakewatersoluble and aredispensedinsoftgelatincapsules.Nowadays, particulate powder. The particlesaresuspendedinoil Micronisation referstocreamywhitecrystalline unnatural. been synthesizedbutitisnotsynthetic,that Progestins Gestodene Norgestrel First generation Ethynodiol Diacetate withoutmissing19-carbon Norethindrone Acetate Norethynodrel Non19-nortestosterone onederivatives Norethindrone With missing19-carbon 19-nor testosterderivatives } 4 , formaintenanceafter Norgestimate Desogestrel Levonorgestrel } } Progestins These arealsoclassifiedgenerationwise. according tosteroidfromtheyarederived. These arederivedfromsteroidsandfurtherclassified Synthetic progesterones: No changeincoagulationprocessorbloodpressure. tenderness, moodchangesetc.areless. Typical ‘progesterone’ sideeffects ofbloating,breast determines theirmolecularstructure. the steroidfromwhichtheyarederived,then Progestins areclassifiedintofourgenerationsbasedon Classification: Newer andOlder Progestins Usesofsyntheticprogesterones: .Hormonereplacementtherapy Premenstrualsyndrome 5. Contraception 4. Endometriosis 3. Abnormaluterinebleeding 2. 1. Second generationprogestins Newer Fourth generationprogestin Drosperinone (Spironolactonederivative) Medroxy progesterone 17 hydroxy progesterone Newer Third generationprogestins very fewtypical‘progesterone’ sideeffects. activity whichdoesnotcause waterretentionandhence activity. Itsbenefitisthatithasanti mineralocoticoid only progestogenicactivity butalsoithasantiandrogenic drosperinone isaSpironolactonederivative.Ithasnot The newermostfourthgenerationprogesterone, activity. derivative, Medroxyprogesteronewhichhaslowsuch androgenic effects exceptthehydroxyprogesterone The firstandsecondgenerationprogesteronesexertanti hepatic serumproteins. counteract thestimulatingeffect ofethinylestradiolon desogestrel andmaymoderatelyreduceSHBGlevels The mostpotentprogestogensaregestodeneand ethinyl groupatC17. belong tothesubgroupof13-ethyl-gonaneswithan derivatives. Desogestrelnorgestimate andgestodene All thesenewerprogestinsare19-nortestosterone norgestimate (precursorof levonorgestrel) areprodrugs. desogestrel (precursorof3-keto-desogestrel)and pharmacokinetic propertiesandhormonalactivities.Both great variationbetweentheseagentsintheir having weakornoandrogeniceffects. However, thereis norgestimate, gestodenesharethecommonpropertyof Structure and Activities oftheProgestins The newerprogestogens,namely, desogestrel, 5 References Conclusion .Stanczyk FZ.Pharmacokinetics andpotencyof 2. Allen WM. The isolationofcrystallineprogestin. 1. Initial datasupportsthattheneweragentsarewell- The progestinsavailableforcontraceptionarenot Progestogens encompassbothnaturalandthe Progesterone actsasaprecursortomanysteroid management. Drosperinone maycreaterevolutioninPCOS activity alongwithanti-androgenicof tolerated andsuperaddedantimineralocoticoid similar. endogenous progesterone. synthetic compoundswhichmimictheactionsof metabolic effects inthebody. andregulatesmanybiological Disord 2002’3:211-24. therapy andcontraception. RevEndocrmetab progestins usedforhormone replacement Science 1935:82:89-93.

25 FOGSI FOCUS 26 FOGSI FOCUS .KrattenmacherR.Drospirenone:Pharmacology 5. ACOGCommitteeOpinionNo.419.Useof 4. .Sitruk-Ware R,SmallM.KumarN,etal. 3. Contraception 2000;62:29-38. and Pharmacokineticsofauniqueprogestogen. ObstetObstetGynecol 2008;112:963-5 College ofObstetriciansandGynecologists. progesterone toreducepretermbirth. American 13 contraception andHRT. Steroids 2003;68:907- nestorone r clinicalappli-cationsfor INTRODUCTION: labour concentrating ontherole ofprogesterone inpreterm preparations as wellbutinthischapter, wewillbe Itisanimportantcomponentofmanycontraceptive TechniquesReproductive Assisted Multiplepregnancyand Pretermlabour RecurrentPregnancyLoss LutealPhaseDefect Its immunological effects onfetalandmaternaltissues. maintenance throughitsendocrine,paracrineand steroid ketoneisanundisputedmoleculeinpregnancy SAFE MOTHERHOOD PROGESTERONE FOR prevention ofpretermbirth, andrepresentsthefirst time thattheFDAhasapproved amedicationforthe previous spontaneouspreterm delivery. This isthefirst preterm birthinwomenwith ahistoryofatleastone OHP-C) duringpregnancytoreducetheriskofrecurrent supplementation (17hydroxyprogesteronecaproate,17- Administration (FDA)approvedtheuseofprogesterone Jubilee MissionMedicalCollege, Dr. NeethaGeorgeM.S,D.G.O role insafemotherhood Progesterone otherwiseknownasprogestational [email protected] On February3,2011, theUSFoodandDrug Consultant inOBGYN, Thrissur, Kerala.

includes itsusein (MFMU) Trial Development (NICHD)MaternalFetalMedicalUnits In the17-OHP exposedinfants 0.91]) Delivery<32weeks (11% v20%[RR,0.58;95%CI0.37- 0.93]) Delivery<35weeks (21%v31%[RR,0.67;95%CI0.48- 0.81]) Delivery<37weeks(36%v55%[RR,0.66;95%CI0.54- (RR=relative risk,CI=confidenceinterval) delivery intheprogesteroneexposedwomen 16-20 weeksuntil37weeks. wererandomizedtoweekly17-OHPorplaceboat high riskforpretermbirthbecauseofaprior progesterone inreducingpretermbirth. What doesEvidenceBasedMedicineSay? almost 15years approval ofadrugspecificallyforuseinpregnancy The NationalInstituteofChildHealthandHuman There wassignificantlyreducedriskofpreterm supplemental oxygen, intraventricular hemorrhage andneedfor Reduced ratesofnecrotizing enterocolitis, Less perinatalmortality, (1) (2)

[email protected] Thrissur. Jubilee MissionMedicalCollege, Senior Resident, Dr. ElavarasiElamaranD.G.O showedtheeffectiveness of

there was

463 patientsat 4

27 FOGSI FOCUS 28 FOGSI FOCUS 17-OHP pluscerclagereducedrisks decreases pretermlabor(PTL)risk.Itwasfoundthat to seeif17-OHPwomentreatedwithcerclage typically treatedwithcerclage injections of17-OHP, andcervicalinsufficiency is suppository (100mg)orplacebonightlyfrom24to34 who wereadministeredavaginalprogesterone (PTB), prophylacticcerclage,oruterinemalformation) delivery (ahistoryofpriorspontaneouspretermbirth published anRCTof157womenathighriskforpreterm MECHANISM OFPROGESTERONEINPTL: RECENT RANDOMISED TRIALS ONPROGESTERONE Prior Pretermlaboristypicallytreatedwithweekly de Fonsecaandcolleagues offspring. There wasnoevidenceofvirilizationfemale . Dr. Temming etal (Brazilian Trial) (3) wanted admission, lowbirthweight,anddurationofNICUstay. P in thefirstgroupcomparedtocontrols(39.2%vs59.5%, delivery. This studyfoundareductioninpretermbirth day fromrecruitment(18–24weeks)until36weeksor mg oforalmicronizedprogesteroneorplacebotwicea women withatleastonepretermbirthwhoreceived100 randomized double-blind,-controlledtrialof150 compared to18.6%intheplacebogroup. oflessthan34weeksintheprogesteronegroup to 28.5%intheplacebogroupanda2.8%rateofpreterm of lessthan37weeksintheprogesteronegroupcompared weeks. This studyfounda13.8%rateofpretermbirths - .0002). There wasalsoareducedriskofNICU In2009, Table1 (6) Rai andcolleagues (5) (4)

conducteda ripening associated withcervical and COX-2,whichare nitric oxidesynthase(iNOS) decreases levelsofinducible progesterone contractile whilenotalteringthelevelsofcirculating progesterone withdrawal,makingtheuterusmore at term,whichmayagainleadtoafunctional progesterone receptorcoactivatorsinthepregnantuterus gene which inhibitconnexion43andoxytocinreceptor and ZEB2(zincfingerEboxbindinghomeoboxprotein) activity ProgesteronestimulatestranscriptionofZEB1 induced blockingfactordecreasedecidualNKcell in laborwasstimulatedbythe collagen inthedilatedcervix Degradation oftype I act atthelevelof quiescent. ratio whichmakesuterus PR-B (progesteronereceptor) progesterone decreasePR-A/ cyclooxygenase-2 (COX-2)–inducedcontractilityinthe antagonizes nuclearfactor- K-Beta-activationof uterus byinhibitinguterinecontractions preterm births progesterone mayprevent another mechanismbywhich inflammation, postulating presence andabsenceof the cervix,bothin modulate geneexpressionin agents havebeenfoundto uterine quiescence progesterone receptortoregulategenesthatlead may berelatedtothedecreasingabilityof “functional progesteronewithdrawal.” changes intheuterusthatarethoughttoleada promote contractions. There aremanybiochemical of progesteronepreventcontractionsandlowlevels initially proposedasasee-sawtheoryinwhichhighlevels Progesteronemayalso Administration of It hasbeenshownthattheprogesteronereceptor Progesteroneisthoughttoenhancequiescenceofthe Indeed, thisfunctionalwithdrawalofprogesterone .(13) (10). .(14)

(15) Condon .Progesterone . Progestational (11). Progesterone causes Th2 shift, .(8,9) demonstrated adeclineinlevelsof .(16) .(7) This was This (12) P enhance productionofprostaglandins diminishes productionofIL-11, acytokineknownto shown thattheadditionofprogestintotermdeciduacells decidua cellsfrominducedcelldeath been showninvitrotoprotectfetalchorionandhuman controls of IL-6wassignificantlydecreasedcomparedwith (LTA) orlipopolysaccharide(LPS)stimulatedinduction who receivedexogenous17-OHP-C,lipoteichoicacid suppresses thematernalimmuneresponse.Inpatients research. Studies havefoundthatgiving17-OHP-C infection cervical ripeningandactsasbarriertoascending Progesterone decreasesstromaldegradation,inhibits regulated byprogesteroneatthetranscriptionallevel. production inuterinecervicalfibroblastsisdown- LABOUR SUMMARY OF PROGESTERONEINPRETERM progesterone This processwasblockedbytheadditionof addition ofphysiologicconcentrations17-. The maternalimmuneresponseisanotherareaof Basal andinterleukin-1(IL-1)inducedIL-8 .(20) .(17,18,19) The additionofexogenousprogesteronehas (23) .(17,18,19) . (22) .(21) It hasbeen

29 FOGSI FOCUS 30 FOGSI FOCUS effect inthe initiationofhumanlabor progesterone, suggestinganautocrineandparacrine hormone (ACTH)bothworktodown-regulate end ofgestationandshowCRHadrenocorticotropic have investigatedtherisingfetalcortisollevelsat production andprogesteronepreventingit.Otherstudies pregnant uterus,withcortisolincreasingprostaglandin Cortisol andprogesteronehavecompetingeffects onthe “placental clock”tocontrolthetimingofparturition of bothtermandpretermlaborinhumans,actingasa labor. RisinglevelsofCRHarenoted toprecedetheonset releasing hormone(CRH)inthetimingandinitiationof Research suggestsaroleforplacentalcorticotropin- Lastly, theremaybeautocrineandparacrineeffects. Table 3 (23) .(25,26,27) (24). days forpresenceofotherfactorsPTL. measurements 21-25mmarere-examinedoncein7-14 Cerclage shouldbedoneinthesecases.CL morbidity andmortality, andcanbeoffered inthesecases. is associatedwithreductioninPTBandperinatal progesterone, either90-mggelor200-mgsuppository, and short TVU CL<20mmat<24weeks,vaginal 2.Inwomenwithsingletongestations,nopriorSPTB, PTB, andunknownCL. of progestogensinsingletongestationswithnoprior 1. There isinsufficient evidencetorecommendtheuse (Society ForMaternoFetalMedicine( Summary ofrecommendations of ACOG andSMFM - PROGESTERONE FOR THE PREVENTIONOF when andhow? 23,28) expression inmyometrialcells invitro does notinhibitstretch-induced MAPKactivationorgene is supportedbyarecentstudy showingthatprogesterone stretch—is different fromthatinsingleton. This argument and deliveryinmultiples—namelyexcessiveuterine suggests thatthemechanismleadingtopretermlabor does notpreventpretermbirthinmultiplepregnancy The observationthatprogesteronesupplementation prevention ofPTBinmultiplegestations,orPPROM. 5.Progestogenshavenotbeenassociatedwith weeks, cervicalcerclageshouldbeoffered. women, ifthe TVU CL shortensto<25mmat<24 20 weeksuntil36isrecommended.Inthese weeks, 17P250mgIMweeklypreferablystartingat16- 4. InsingletongestationswithpriorSPTB20-366/7 Unexplained vaginalbleed<14weeks TAS CL <3cm24wk cramps, pelvicpressure,changeinvaginaldischarge Current pregnancysymptoms-premenustrualsymptoms, Current pregnancyriskfactors All AfricanAmericans Women whosmoke,aredepressed,orBM1<19.6 Uterine anomalies History ofcurrentgenitourinaryinfection History of1ormorepregnancytermination History ofcervicalinstrumentation All pregnanciesconceivedafterinfertilitytreatment All womenwithriskforPTL-RR>1.5 All womenwithpriorPTL SCREENING: RECOMMENDATIONS FOR TVU CL weeks alongwithcerclage. mg suppositories,forshort TVUCL <20mmat<24 offering vaginal progesterone,either90-mggelor200- to screenlow-risksingletongestationsmayconsider should followstrictguidelines.Practitionerswhochoose who decidetoimplementuniversal TVU CL screening be consideredbyindividualpractitioners.Practitioners screening strategycanbeviewedasreasonable,and mandated. Nonetheless,implementationofsucha gestations withoutpriorPTBcannotyetbeuniversally remains anobjectofdebate.CLscreeninginsingleton gestations withoutpriorPTBforthepreventionof 3. The issueofuniversal TVU CL screeningofsingleton (29) : . absence ofundesirableside effects. Vaginal progesterone more absorption,enhanced bioavailabilityandthe vaginally, butthelatterrouteispreferable becauseof progesterone canbeadministered eitherorallyor serum concentrationafter vaginal dosing.Micronized a 14timesgreaterincreaseintheratioofendometrial to concentration thanviaintramuscularadministration,with to itsnaturalformulationandhigherendometrial recommended. Authors favoringthisformulationpoint administered daily. Dosesof90to400mghavebeen a half-lifeofapproximately13hours. It shouldbe release butoptimalbloodlevels.Vaginal progesteronehas with improvedfetal,neonataland/orinfantoutcome to clinicaltrialsdeterminewhetheritsuseisassociated delivery, progesteroneadministrationshouldberestricted recommendations that,inwomenathighriskofpreterm Gynaecologists (RCOG)endorsescurrent of pretermlabourinlowriskpopulation. preterm birthpreventionwithpositivefFNwithoutsigns supplemental progesteroneisnotatpresentindicatedfor gestation isonly13%and36%,respectively. Therefore preterm deliverypriorto28weeksand37of fFN testat22to24weeksofgestationforspontaneous risk population,thepositivepredictivevalueofa an increasedriskofpretermbirth.However, inalow- through 34-6/7weeksofgestationareassociatedwith cervicovaginal fFN(definedas>50ng/mL)at22-0/7 cervicovaginal secretions. Elevated levelsof the measurementoffetalfibronectin(fFN)in College ofObstetriciansandGynecologists(ACOG)is FDA approvedandrecommendedby The American predictors forpretermbirth corticotrophin-releasing hormone,andactivin A) are 8.Biochemical andendocrinemarkers(includingestriol, suppression ofpituitaryLHsecretion. frequently resultsinpoorlutealfunctiondueto orantagonistusedtopreventprematureLHsurge progesterone supplementationisessentialsinceGnRH 7. Forpatientsundergoing assistedreproduction, tocolysis progestogens forprimary, adjunctive,ormaintenance 6. There iscurrentlyinsufficient evidencetorecommend has notyetbeendetermined. delivery, anddoseforthepreventionofpretermbirth Administration ofProgesterone: Intramuscular progesteronepreparationshaveslow The RoyalCollegeofObstetriciansand The optimalprogesteroneformulation,routeof . The onlytestthatiscurrently (30-33) .

31 FOGSI FOCUS 32 FOGSI FOCUS discontinuation inonly0.6%patients. urticaria (3.1%),butimportantlyleadingtodrug progestogens, includinginjectionsitereactionsand Sideeffects arefairly commonwithinjectable Side effects: SAFETY OFPROGESTERONE: preparations mayhavemorecompliance Fororalpreparations,300mgsustainedrelease or 90mg8%gelnightly. progesterone capsulesvaginallynightly(compounded) progesterone, adoseofeither100to200mgmicronized available withequalefficacy. Ifoptingforvaginal OHP-C ,thoughnaturalprogesteronepreparationsare widely studieddoseis250mgweeklyintramuscular17- isvaginaldischarge in8-9% common complaintamongusersofvaginalprogesterone treatment dependsontheindication Timing ofInitiationandCessationProgesterone and lesslocaldiscomfort. OHP anditsmetabolitesdocrosstheplacenta. placenta, significantconcentrationsofexogenous17- appropriate. Although activelymetabolized inthe weekly dosingwouldseemmost approximately 7days, of gestation.Becausethehalf-life17OHPis 5 daysto1000mgweekly, beginningasearly16weeks intramuscularly. Doseshaverangedfrom250mgevery placenta. Exogenous17-OHPisadministered activity thatisproducedbyboththecorpusluteumand .17-OHP isanaturalprogesteronewithnoandrogenic of progestinwiththeindicationpreventionPTL and Drug Administration (FDA)approvedformulation progesterone withleastsideeffects oforalpreparations 300mg or400mgcandeliverahighconcentrationof first passeffect. bypass hepaticmetabolismthereforehasvaginouterine

Risk ofcongenitalmalformations: preparations. preparations thanwithvaginal andoralsustainedrelease gastrointestinal disturbancesaremorewithoralplain side effects suchassleepiness,,headachesand Dose ofProgesterone The optimaltimingforinitiationofprogesterone Gelordispersibletabletshavebetterbioavailability Currently, intramuscular17-OHP istheonlyUSFood Recent formulationsofsustainedreleasepreparations There isalarge bodyofliteratureontheuse When optingforintramuscularprogestin,themost (34-36) : (33). .(6) Other undesirable Other (37) The most : . 1. Advances inthepreventionofspontaneouspreterm 3. There arestudieswhichshowthatalteredcalcium 2. There isrisingevidencethatPCOSaleadingcause is limitedtoexposureprior11 weeksofgestation to exogenousprogestins,evenifreal,however, thisrisk increased riskofhypospadiasinmaleoffspring exposed found. The onlyconcernthatpersistsisapossible 2. Paul J.Meis,MarkKlebanoff, Elizabeth Thom, Aaron BCaughey Louis E.Phaneuf, Errol RNorwitz, 1. individualised. SPTB shouldbeevaluatedandthetreatment preterm birthinone-thirdofsubjects. The reasonsof supplementation hasbeenshowntopreventrecurrent reproduction progestins inthefirsttrimesterforassisted REFERENCES: NEWER CONCEPTS: MICA2, SMTL2,andDESP including SPTA2, GA2L2,DMD,SYNE1,NOS1, frequencies betweenrespondersandnonresponders; oxide synthasepathwaywithdifferent allele risk ofprimarySPTB. There are8genesinthenitric 17-OHP duringtheirfirstpregnancycouldreducethe could bestudiedtodeterminewhethertreatmentwith preterm birth),thosewomenwithahigh-riskgenotype history ofmulleriananomaliesorafamily other riskfactorsforpretermbirth(suchasapersonal this strategyisappliedtonulliparouswomenwith individualized preventionregimencanbeoutlined.If prospectively bygenotypeandifanappropriate most likelytorespond17-OHPcanbeidentified birth (SPTB)with17-OHPcanbemadeifwomen influxthroughvoltagegatedCachannels Progesterone offers protectiverolebydecreasing offetalmembranesespeciallyinPPROMand homeostasis leadstocelldeathinchorionanddecidual cerclage inpatientswithshortcervix. PTL inthesepts.,butdoesn’t replacetheroleof supplementation preventsonsetofmiscarriageand of cervicalincompetenceandPPROM.Progesterone progesterone Caproate, NEnglJMed2003; of RecurrentPretermDelivery by17 Alpha-Hydroxy Mitchell P. Dombrowski,BahaSibai etal;Prevention Summer; 4(2): 60–72. of pretermbirth;RevObstetGynecol. 2011 et al;Progesteronesupplementationforprevention To summarise, (38-40). Novirilisationoffemalefetushasbeen

in idealcandidates,progesterone . (41) (42) ( 1) (43) 12. BumChaeChoi,Katalin Polgar, LingXiao,Joseph 11. CondonJC,JeyasuriaP, FaustJM,etal. A declinein 10. HardyDB,JanowskiBA,CoreyDR,MendelsonCR with the‘functionalprogesteronewithdrawal’.MolHum factor-kappaB activitywhichmediatescyclo-oxygenase- 9. Allport VC, PieberD,SlaterDM,etal.Humanlabour 8. Zakar T, HertelendyF.Progesteronewithdrawal:key caproate, inhibitshumanmyometrialcontractions. Am J 7. RuddockNK,ShiSQ,JainS,etal.Progesterone,but 6. CarlaE.Ransom, Amy P Murthaetal.Progesterone 5. RaiP, RajaramS,GoelNetal,oralmicronized 4. EduardoB.Fonseca,EbruCelik,MauroParra, ACOG newsletter,May6,2013. Temming3. Lorene 17P etal, PlusCerclageDecreases Thl cytokineproductionto trophoblast inwomenwith A.Hill etal;Progesteroneinhibits in-vitroembryotoxic 2003;100(16):9518–23. initiation ofparturition.ProcNatl Acad SciUSA progesteronereceptor functionandcontributetothe pregnant uterusattermmayantagonize the levelsofprogesteronereceptorcoactivatorsin expression. Mol.Endocrinol20:2724-2733 antagonism ofNF-KbactivationCOX-2 inflammatory roleinhumanmyometrialcellsby et al.Progesteronereceptorplaysamajoranti Reprod 2001;7(6):581–6. 2 expressionandisinvolved is associatedwithnuclear 96. LevelII-2 to parturition. Am JObstet Gynecol2007;196:289- Obstet Gynecol;2008;199(4):e391. not 17-alpha-hydroxyprogesterone Am 39(2012);1–16doi:10.1016/j.ogc.2011.12.004 for PretermBirthPreventionObstetGynecolClinN j.ijgo.2008.08.029. Gynaecol Obstet2009Jan;104(1):40-3.doi:10.1016/ progesterone forpreventionofpretermbirth;IntJ 10.1056/NEJMoa067815 . Engl JMed2007;357:462-469 August 2,2007DOI: Preterm Birthamong Women withaShortCervix;N Screening Group;ProgesteroneandtheRiskof Fetal MedicineFoundationSecond Trimester Mandeep Singh,KyprosH.Nicolaidesetalforthe Preterm LaborRisk NEJMoa035140 348:2379-2385June 12,2003DOI:10.1056/ . 23. SMFM Clinical Guideline; Progesterone andpreterm 23. SMFMClinicalGuideline; 22. CakmakH,SchatzF, HuangST, etal.Progestin 21. Murtha AP, FengL, Yonish B,etal.Progesterone 20. FogliaLM,IppolitoDL,Stallings JD,etal. 19. CarlaRansometal,Progesteronesupplementation 18. Ito A, Imada K, Sato T, etal.Suppressionof 17. RajabiMR,DodgeGR,SolomonS,etal. 16. XuH,GonzalezJM,OforiE,etal.Preventingcervical 15. MarxSG, Wentz MJ,MackayLB,etal.Effects of 14. Zakar T ,MesianoS.Howdoesprogesteronerelax 13. PeltierMR, Tee SC,SmulianJC.Effect of Gynecology 383MAY 2012. birth prevention; American JournalofObstetrics Metab 2005;90(9):5279–86. implications forpretermdelivery. JClinEndocrinol interleukin-11 productionintermdecidualcells: suppresses thrombin-andinterleukin-1beta-induced 2007;196(3): 257.e1–5. calcium-induced . Am JObstetGynecol protects fetalchorionandmaternaldeciduacellsfrom Obstet Gynecol2010;203(6):561,e1–5. maternal peripheralbloodmononuclearcells. Am J administration attenuatesimmunoresponsivenessof Intramuscular 17alpha-hydroxyprogesteronecaproate (2012doi:10.1016/j.ogc.2011.12.004.) , ObstetGynecolClinN Am 39 in womenwithotherwiseunexplainedrecurrent uterine cervix.BiochemJ1994;301(Pt1):183–6. interleukin 8productionbyprogesteroneinrabbit 1991;128(1):314,1–8. of cervicaldilatationintheguineapigatparturition. of estrogen-mediatedcollagenolysisasamechanism Immunochemical andimmunohistochemicalevidence Obstet Gynecol2008;198(3):e311– 8. progestational agentspreventpretermbirth? Am J ripening: theprimarymechanismbywhich 2006;54(6):623–39. expression inthecervix.JHistochemCytochem progesterone oniNOS,COX-2,andcollagen 364:972–973 the uterusinpregnancy?.NEnglJMed2011; 2008;60:346–353 with pretermbirth. Am JReprodImmunol. by monocytesstimulatedwithpathogensassociated progesterone onproinflammatorycytokineproduction 1208.106335 . 248–251.doi:10.4103/0974- Sep-Dec; 5(3): recurrent pregnancyloss;JHumReprodSci. 2012 . LevelII-2 . &

33 FOGSI FOCUS 34 FOGSI FOCUS 28. American CollegeofObstetriciansandGynecologist. 27. KaralisK,GoodwinG, MajzoubJA.Cortisol 26. JeschkeU,MylonasI,RichterDU,etal.Regulation 25. ChallisJR,SlobodaDM, Alfaidy N,etal. 24. .McLeanM,Bisits A, DaviesJ,etal. A placental 35. CicinelliE,deZiegler D,BullettiC,etal.Direct 34. BullettiC,deZieglerD,Flamignietal. Targeted 33. O’BrienJM, Adair CD,Lewis DF, etal.Progesterone 32. MajhiP, BaggaR,KalraJ,etal.Intravaginaluseof 31. DoddJM,CrowtherCA,McPhee AJ, etal. 30. DeFrancoEA,O’BrienJM, Adair CD,etal; Vaginal 29. Joel.D.Larma,JayDIamsetal;Issonographic 2003;102:1115-6. ofObstetrics committee opinionNo.2919.ObstetGynecol Use ofprogesteronetoreducepretermbirth: ACOG Nat Med1996;2(5). mechanism involvedintheinitiationofhumanlabor. blockade ofprogesterone:apossiblemolecular Arch GynecolObstet2005;272(1):7–12. in vitrobyCRH, ACTH andcortisol(). productioninhumantermtrophoblasts progesterone of Reproduction 2002;124(1):1–17. andmechanismsofpretermbirth. Med 1995;1(5):460–3. clock controllingthelengthofhumanpregnancy. Nat Gynecol 2000;95(3):403– 6. transport ofprogesteronefrom vaginatouterus.Obstet effect. HumReprod1997;12(5):1073–9. drug deliveryingynaecology:thefirstuterinepass 2007;30:687-96. placebo-controlled trial.UltrasoundObstetGynecol primary resultsfromarandomized,double-blind, vaginal gelforthereductionofrecurrentpretermbirth: 2009;29(6): 493–8. birth: arandomisedtrialinIndia.JObstetGynaecol natural micronisedprogesteronetopreventpre-term Pregnancy Childbirth2009;9:6. (PROGRESS): arandomisedcontrolledtrial.BMC prevention ofneonatalrespiratorydistresssyndrome Progesterone afterpreviouspretermbirthfor Gynecol 2007;30:697-705 in womenwithashortcervixUltrasoundObstet early pretermbirthandimprovedneonataloutcome progesterone isassociatedwithadecreaseinriskfor GRF.0B013e3182487e96. Obstetric Gynecolvol.55,no.1,324-335.doi:10.1097/ assessment ofcervixnecessaryandhelpful?Clinical May 2012. & Gynecology; 383 43. Murtha AP, FengL, Yonish B,LeppertPC, 42. Feigenbaum SL, Crites Y, Hararah MK, Yamamoto 41. Tracy A Manuck,Scott Watkins, BarryMooreetal. 40. Yovich JL, Turner SR,DraperR. 39. ResseguieLJ,HickJF, BruenJA,etal.Congenital 38. KatzZ,LancetM,SkornikJ,etal. Teratogenicity of 37. RouseDJ,CaritisSN,Peaceman AM, etal. A trialof 36. DeZieglerD,BullettiC,MonstierB,etal. The 257.e5. death. Am JObstetGynecol2007;196:257.e1- and maternaldeciduacellsfromcalciuminduced Schomberg DW. Progesteroneprotectsfetalchorion humrep/des193. Reprod. sep2012;27(9):2837-42.doi:10.1093/ insufficiency inPolycysticovariansyndrome;Human MP, Yang J,LoJCetal , prevalanceofcervical Gynecol 2014;210::321.e1-21. recurrent pretermbirthprevention. Am JObstet Pharmacogenetics of17alphahydroxylcaproatefor 1988;38(2):135– 44. pregnancy hasnoapparentfetaleffects. Teratology Medroxyprogesterone acetatetherapyinearly Fertil Steril 1985;43(4):514–9. progestins, OlmstedCounty, Minnesota,1936–1974. malformations amongoffspring exposedinuteroto pregnancy. ObstetGynecol1985;65(6):775– 80. progestogens givenduringthefirsttrimesterof 61. prematurity intwins.NEnglJMed2007;357(5):454– 17 alpha-hydroxyprogesteronecaproatetoprevent 1997;828:291–9. first uterinepasseffect. Ann NY Acad Sci of theirrouteadministration: All progesteroneonlycontraceptive methods,regardless Mechanism ofaction: vaginal rings. implants, injectables,intrauterinehormonalsystems,and progesterone usewereconsideredas:oralprogestins, As aresultofthisendeavor, variousmethodsforthe clinical sideeffects associatedwiththeuseofestrogens. have acontraceptivemethoddevoidofthemetabolic or than 30years.Itwasrecognizedtoplaythisrolesoas to Progesterone hasbeenusedforcontraceptionmore this “cafeteriaapproach,”sincethe1960s. considerations. The Family Welfare Programhasadopted safety, non-contraceptivebenefits,cost,andpersonal contraceptive methodinvolvesfactorssuchasefficacy, that wouldberightforthem. A patient’s choiceof informed tothecoupleallowingthemmakeadecision woman tochoosefrom. All thedevicesavailableare cafeteria approach Contraception isachoicetopreventconception. The Introduction: IN CONTRACEPTION PROGESTERONE CAFETERIA .Reduce spermtransport 3. Reducesperm penetrability 2. Affect cervicalmucus,makingithostile 1. FRCOG (UK)FRCPI(IRL)FICOG, President FOGSI&ICOG2014 Prof. Dr. SuchitraN.Pandit MD., MAO(IRL)DGO,DFP, President MOGS(2013-14) FICMCH, PGD,MLS(Law) offers abouquetofproductsfor

hypothalamic-pituitary-gonadal-genital tractaxis. in diversetarget cells,whicharedistributed alongthe These progestinsactbybinding totheirreceptorslocated activity anddose. Mechanism ofactioneach dependsonprogesterone

.Compromiseendometriumfoeimplantation 5. Inhibitovulation 4. 1 M.Y Hospital,Indore(M.P) M.G.M MedicalCollege Dept. ofObs&Gyn MS OBG Dr. SwatiBhargav 5

35 FOGSI FOCUS 36 FOGSI FOCUS rate forPOPusersis0.3%. Clinical effectiveness: the sametimeeveryday. progestin thanthecombinationpill.Ithastobetakenat The pillscomeinpacksof28andcontain35-75%less . feasibility offormulationsforlong-termuseandalsoas contraindications toestrogen,,andcomfort situations, whichhaveabsoluteorrelative Progestin-only contraceptivesmaybepreferableinsome progestin-only pills(POPs). as contraceptive. They areoftencalledasminipillsor Numerous progestinonlypillsforcontraceptionareused Oral Contraceptives: In additiontooralcontraceptives, Implants: For typicaluserateofeffectiveness isalmost92%. years. 70 µg/day. containing 68mgofthedrug. The initialreleaseis60- µg .The3-keto-desogestrelimplantisasinglerod levonorgestrel respectively. The dailyrelease ofis50 or 2innumber, eachcontaining36mgor70of implants consistofthedrugenclosedinsilasticrods,6 metabolite, 3-keto-desogestrel. The levonorgestrel implants consistoflevonorgestrel ordesogestrel effective thanoralandbarriercontraceptives. The subdermally forcontraceptivepurpose. They aremore contraception in1990. These aremainlyused Norplant wasreleasedasanimplantformof This reducesto25-30µg/daybytheuseof3 With perfectuse,thepregnancy 2 implants arealsoused. With perfectuse,thepregnancyrateDMPA is0.3%. Clinical effectiveness: administration. be detectedinsystemiccirculationwithin30minof of depotmedroxyprogesteroneacetate150mg.Itcan It isadministeredevery3months,eachcontainingadose contraceptive. cafeteria. The FDA approvedit,in1992asaninjectable injectable progesteronealternativeincontraception Depot MedroxyProgesterone Acetate Injectable contraceptives: As spermsareviableforseveraldays,andwomencan’t 72 hours. after shehashadunprotectedintercourse,ideallywithin It ishormonalcontraceptionthatusedbyawoman Emergency contraception be given. bone mineraldensity, socalciumsupplementation must Black boxwarning: Women usingDMPA mayloose For typicaluserateoffailureisalmost3%. use is0.05. Failure rateforimplantswithbothperfectandtypical Clinical Effectiveness: incision underlocalanesthesia. Formulations areimplantedsubdermallywithminimal 5 andwithdesogestrelis3years. The contraceptiveefficacy oflevonorgestrel implantsis 2 among women. effectiveness oflactational It isusedtoextendthecontraceptive doses. of levonorgestrel tobeaseffective astwo WHO recommendssingle1.5mgdose within 72hours. same dose12hourslater, both doses unprotected intercoursefollowedby advised assoonpossibleafter One doseof0.75mgLevonorgestrel is contraceptives. mode ofactionemergency or delaysovulation. This istheprincipal by acontraceptivemethodthatblocks it maybepossibletopreventfertilization be sureoftheexacttimingovulation, Progesterone vaginalring (DMPA) is agood 2 Other advantagesofLNG-IUS siloxane membraneintouterine cavity. 20mcg ofhormoneperdaythroughpoly-dimethyl- of about52mgLevonorgestrel (LNG).Itreleases A cylindricalreservoiriswrappedaroundverticalstem T-shaped frameimpregnatedwithbariumsulphate. Levonorgestrel. Itcontains32mmlong,flexibleplastic LNG-IUS isthehormonalintrauterinesystemcontaining Intrauterine progesterone contraceptive(LNG-IUS) sexually transmittedinfections,includingHIV. The progesteroneringdoesnotprovideprotectionfrom walls—approximately 10mgperday. a continuousflowofprogesteronethroughthevaginal continuously foruptooneyear. Itfunctionsbydiffusing contraception isdesired. Women canusetheserings a newringifbreastfeedingiscontinuedandextended continuous useforuptothreemonthsandreplacedwith Progesterone vaginalringsareinsertedinthevaginafor .Reduction inmenstrualpain 2. Reduction inmenstrualflow 1. 3 typical use. Pregnancy failurerateis0.1%onperfectaswell efficacy getsover. After 5yearsitshouldberemovedasitscontraceptive Clinical effectivess: Pregnancy mustberuledout. Difficulties duringinsertionarereported. Precautions: attention tomarkitsimportanceinthisfield. emergency contraceptionandothertimes,drawsthe rings todevices.Itsuseatvariedperiodslikelactation, contraception rangingfromoral,injectable,implants, approach ofProgesteroneuseasamethod Thus thereareavastvarietyofoptionsinthecafeteria Disadvantages References ptigcommon) Follicularcysts Implants Injectables Amenorrhea Breast spotting Irregularbleeding Intermenstrual Irregularbleeding Irregular bleeding Oral Side effectsofprogesterone contraceptiveagents .Romer T, Linseberger D.Usersatisfactionwitha 3. .LandgrenBM.Mechanismofactiongestagens, 1. .Trusell J. The essentialsofcontraception: 2. .Reductioninendometrialhyperplasia/cancer. 4. Reductioninsizeoffibroid. 3. .Theneedtobeinserted/removedbyaclinician. 3. NoprotectionagainstSTIs 2. Highcostofinsertion 1. reproductive healthcare Europeaon JournalofContraceptionand IUS): datafromaninternationalsurvey, levonorgestrel-releasing intrauterinesystem(LNG- 2004. RA,Stewart F, etaleds,New York: Ardent Mediaa, Int JGynecolobstet Contraception Technology efficacy,safety andpersonalconsiderations.In 2 : density in bonemineral And Reduction 1990;32:95-110 edresInfection(Less tenderness 2009;14:391-8 18 th reviseded,Hatcher The

37 FOGSI FOCUS 38 FOGSI FOCUS Beams Hospitals,JubileeHills,Hyderabad Chief Laparoscopicsurgeon,Obst&Gyn, use ofProgesteroneinthose conditions. need ofunderstandingthe Estrogendominance&the affecting closeto10%ofwomen. This necessitates the in 25%ofwomenage35 to40yearsandbreastcancer of perimenopausalwomen,(2)uterinefibroidsareseen 10% ofperimenopausalwomen,PMSisaffecting 30% dropping aslow10years,endometriosisisaffecting menopausal transition. Today ,theageofmenarcheis Estrogen dominancecanstartasearlymenarche to of progesterone. This means - states wherethelevelofestrogenoverweighs Lee. (1)Estrogendominanceisatheoryaboutmetabolic The term‘EstrogenDominance’iscoinedbylateDr. John INTRODUCTION: ESTROGEN DOMINANCE PROGESTERONE –ANSWERTO )thelevelestrogen levelisreducedbutnotceased 3) normallevelofestrogenwithlow 2) estrogencanbehighwithnormallevelof 1) Visiting Consultant–RainbowHospitals, Care Hospitals& Yashoda Hospitals, menopausal transition estrogen dominantstate-asseenduring and progesteroneproductionceasesleadingto progesterone or progesterone or Dr. Manjula Anagani Hyderabad , M.D. CAUSES OFESTROGENDOMINANCE

ANOVULATORY CYCLES LUTEAL PHASEINSUFFICIENCY ADRENAL FATIGUE leads todepletionofmagnesium B. Increasedsugar,fastfood andprocessedfood leads todeficiencyofzinc,,andvitamin to elevatedestrogenlevels. Too muchestrogeninturn neutralization ofestrogeninliver. Deficiencieslead Vitamin B6andmagnesium arerequiredfor magnesium, zinc,copperandBcomplexvitamins): NUTRIONAL DEFICIENCIES(especially Estrogen levels remain foralongtimeintheintestine&thushigher increased reabsorptionofestrogenwhenstools that lowfiberdietcausesconstipationleadingto Estrogen isexcretedinbowel.Studies haveshown fibre diet): POOR DIET(usuallyhighincarbohydrates,low support Stressed/tired adrenalglands) progesterone assomeofitisconvertedtocortisol STRESS (excessiveneedforcortisoldepletes

Lalitha GayathriHospitals D.N.B, Consultantgyn, Dr.Nelakuditi, Anitha :

6

39 FOGSI FOCUS 40 FOGSI FOCUS Table 1(1) estrogen balanceeachother. following tableclearlyshowshowprogesteroneand Progesterone actsasanantagonisttoestrogen. The EFFECT: ESTROGEN EFFECT VERSUS PROGESTERONE DOMINANCE: DISEASES ORPROBLEMS DUEESTROGEN 200 –300:(1). the ProgesteronetoEstrogenratioshouldbebetween According toLateDr. JohnLee–foroptimum health, Growth hormoneusedinlivestockandpoultrycontains Causes endometrium ESTROGEN EFFECT Increase bloodclotrisk Reduces vasculartone function slightly Restrains cancer risk Increase endometrial Increases bodyfat cancer that canleadtobreast Causes breaststimulation proliferate Fibrocysticbreast diseases · · estrogen) made inthefatcells;excesscellsmake OBESITY (inpostmenopausalwomen,estrogenis Estrogen dominance. Consumption ofthesexenoestrogencancause PCV’S andotherplasticizersactasestrogen. fat solubleestrogen.Organochlorides, PCB’S, EXPOSURE: ESROGEN ASAPARTHRT UNOPPOSED OF CONTRACEPTIVES USE OFORAL ORINJECTABLE osteoclast Maintains secretory PROGESTERONE EFFECT Normalize bloodclot Restores vasculartone leading tobonegrowth cancer thus preventingendometrial number ofestrogenreceptors glands bydecreasingthe estrogen-primed endometrial Progesterone controlsthe Helps usefatforenergy cancer breast andprevents Protects againstfibrocystic endometrium Promote osteoblast to function, sufficiency. of emotionalwellbeing andpsychologicalself- Progesterone createsandpromotes anenhancedsense and PMSsymptomscanmemorepronounced. progesterone levelsareinsufficient, estrogendominates Progesterone actsasantagonisttoestrogen. When the leads toirritability. increasing freenorepinephrine,highEstrogenlevels inhibiting monoaminoOxidase(MAO)andthus Acting asaCentralNervousSystemstimulant by DOMINANCE: 3)PREMENSTRUALSYNDROME&ESTROGEN thereby preventingendometrialhyperplasia. cyclic mensesandattenuateendometrialgrowth Estrogen –progestincontraceptiontreatmentinduces of endometrialcancermaybeincreasedbythreefold. is predisposedtoabnormalpatternofgrowth. The risk to unrelentingestrogenstimulation&theendometrium Due tochronicanovulationtheendometriumisexposed 2) PCOS&ESTROGENDOMINANCE: endometriosis etc. and breastcancer, fibroids,anemia,, pathological conditionssuchasinfertility, endometrial Incessant Maturationhasbeenassociatedwithincreased independent precociouspuberty. maturation ofHPOaxisresultingingonadotropic Prolonged orrepeatedestrogenexposurecancauseearly precocious pubertyisexposuretoexogenousestrogen. One ofthecausesforgonadotropinindependent DOMINANCE: 1) PRECOCIOUSPUBERTY &ESTROGEN & REPRODUCTIVE AGE GROUP: I. ESTROGENDOMINANCEINMENARCHIAL Breastcancer · Ovariancysts · Fibroids · Endometriosis · Menstrualdisturbances—irregularandheavy · · CertaintypesofPMSEdema(waterretention), · · : bleeding swings anddepression. Progestogens: , drospirenonehasbeeneffective. containing anti-mineralcorticoidandanti-androgenic be thefirststep. intake andhighfibrediet,adequatevitaminshould normalizing zincandcopperlevels.[ fibrocystic ,helpingusefatasfueland restoring propercelloxygenlevels,protectingagainst facilitating thyroidhormone,servingasanaturaldiuretic, depressant, restoringlibido,normalizingbloodsugar, sufferer. symptoms. biochemical changesthatcausethedistressing ovulation andtheensuringcyclicalendocrine/ tone. Magnesium isrequiredformaintainingnormalvessel Estrogen dominancecausesdepletionofmagnesium& water retentionandvasodilationwhichcausesheadache. dilation isthekeyfactorformigraine.Estrogencauses have lessinsomnia whereas womenwithprogesteronesupplementstendto Women with estrogendominancesleeprestlessly Progesterone servesasanaturaldiuretic. potentially leadingtofluidretention. regulation ofsodiumandpotassiumintheblood, Estrogen altersaldosterone–reninfunctionsinvolving )Depomedroxyprogesteroneacetate(Depo b) Cyclicalprogesterones-from5thdayofthecycle a) Combined oralandcontraceptivepills Assurance andlifestylemodificationswithlowfat Progesterone helpsbyactingasanaturalanti- Progesterone offers manybenefitstothePMS A logicaltreatmentforseverePMS,istosuppress The constrictionofbloodvesselsfollowedbyrebound · Migraine&premenstrualheadache: · Insomniaandsleeplessness: Water· retention: continuous low-gradesymptoms duetothePMS- However, cyclicalsymptoms areoftenreplacedwith would beexpectedtohavegreater treatmentefficacy. have ovulationsuppressant activityandassuch suppression ‘progestogen-only pill’(Cerazette)-all etonorgestrel rod(Implanon)andanovulation progesterone( premenstrual syndromewithprogestogensand significant benefitforthetreatmentofsevere for 20days- A recentmetaanalysisshowedno 3 ) . 1 ]. – Provera), espthose effects areaproblem( leading tohigherdiscontinuationrates&systemicside bleeding tendstobeunpredictableandcanheavy they induceamenorrhoea,butduringtheearlymonths medroxyprogesterone acetate:Ifusedforlongenough the 25thday). (wholetreatment-fromthe5thto from the15thto25thday)( cyclically eitherinthesecondhalf(lutealphasetreatment help torestorenormalmenstrualcycle. 5) AUB AND ESTROGENDOMINANCE: mammary effect ofestrogen. Cyclic administrationofprogesteronemodulatesthe fold inthesepatients. The riskofbreastcancerisincreasedtotwofoldfour which isfollowedbyfacultativeepithelialproliferation. that resultsinhyperproliferationofconnectivetissues, by estrogenpredominanceandprogesteronedeficiency The pathophysiologyoffibrocysticdiseaseisdetermined ESTROGEN DOMINANCE: 4) FIBROCYSTICDISEASEOF BREASTS ANS increase inprogrammedcell death.(5) IUS whichmediateareduction incellproliferation& increase inbiochemicalmodulators inwomenusingLNG stroma ,capillarythrombosis . There seemstobean of endometrialglands,decidualisation endometrium ,thinningofthe, )Levonorgestrel intrauterinesystem-Incidenceof c) Depot preparationofNorethisteroneand Oral route:Progestogentherapyisadministered Use ofprogesteroneeithercontinuousorcyclicalform LNG IUS:causesprofoundchangeswithinthe metrorrhagia ormenometrorrhagia. endometrial hyperplasialeadingtomenorrhagiaor by progesteroneinanovulatorycycleleadsto continuous releaseofestrogensecretionunopposed Majority ofDUBisduetoanovulatorycycles. The expectancy symptoms( thus reducingdepressionassociatedwithPMS PMS ,byimprovingmenorrhagia, side effects is less.Onitsownitmaybenefitthe progestogenic PMSlikephysicalandpsychological +duphaston 10mgD17-D28) protection (e.g.Oestradiolpatches(100mcg) been usedwithestrogenforlongtermendometrial Second-line treatment,oralcyclicalprogestogenhas like sideeffects ofsyntheticprogestogens.Soasa 3 ) 4 ) 3 ) orthroughoutthe

41 FOGSI FOCUS 42 FOGSI FOCUS .Estrogenreleaseddirectlyintotheperitonealcavity 2. Estrogensecretedbyovaryintocirculation. 1. Estrogen inEndometriosisisderivedfromthree DOMINANCE: 6) ENDOMETRIOSIS AND ESTROGEN sources. in reproductiveagegroup. and systemiceffects onbonemakesitlessadvisable possibility ofdelayedresumption ofovulatorycycles Depot provera–veryeffective insymptomsbut effective &are relativelywelltolerated.(6) intermittently repeatedmedicationseemtobe lowdoseestrogen :longterm–around6mthsor Progestogens –aloneorincombinationwith Fig1( mechanism ofactionprogestins intreatment ofendometriosis .Estrogenderivedfromadiposetissue. 3. .Estrogen dependancyis evidencedbyitsgrowth 7) FIBROIDS&ESTROGEN DOMINANCE: Fibroid ispredominantlyan estrogendependenttumor at ovulation. ovulation, inducingamenorrhea. can inhibitpituitarygonadotropinsecretionand inducing decidualization,thenatrophy. Highdoses Progesterone inhibitsendometrialgrowthfirstby Rectovaginal Endometriosis)(8) related pain&Deepinfiltratingendometriosis( LNG –IUS–positiveeffects onendometriosis– ) Fig 2(1) due totechnicaldifficulty ininsertion.6 generally recommendedinfibroidsdistortingthecavity cyclically fromdayofthecyclefor20days. medroxyprogesterone acetate5-10mgisadministered secondary tofibroids.Norethisterone/ tumor . temporarily reducesymptomsandtosizeofthe anovulation . following menopauseanditsfrequentassociationwith tumor beforemenarcheandcessationofthegrowth increased growthduringpregnancy,nooccurrenceofthe potentiality beinglimitedduringchildbearingperiod, LNG- IUS–effective formenorrhagiabutnot Progesterones havebeenindicatedinmenorrhagia The goalsofmedicaltherapyforleiomyomaareto premenopausal levels. low comparedtoestrogenwhichisstillhalfits menopause, thetotalamountofprogesteroneisextremely progesterone estrogendeclinesonlyby35%.By From ageof35to50years,thereisa75%reductionin supplementation ofprogesterone. whereas progesteronehascalmingeffect. estrogen. Estrogenhasanexcitatoryeffect onthebrain dominance. of progesteronelevelleadstoastateestrogen produced duringpregnancy. Followingdelivery, thefall ESTROGEN DOMINANCE: 8) AND Postpartum depressioncanbeeasilytreatedwith The progesteronecounterbalancetheeffects of About 300-400mcgofprogesteronearedaily II. ESTROGENDOMINANCEIN PERIMENOPAUSAL WOMEN:

43 FOGSI FOCUS 44 FOGSI FOCUS The causesforestrogendominancehereare: MENOPAUSAL WOMEN: III. ESTROGENDOMINANCEIN Progesteroneservesaroleinkeepingbrain cells · Naturalprogesteronecanbebeneficial toboththose · Naturalprogesterone ispreferredinperimenopausal · Manyperi-orpost-menopausalwomenwithclinical · WITH ESTROGENDOMINANCE: MENOPAUSALMENOPAUSALPOST AND WOMEN PROGESTERONES TREATMENT INPERI .Useofunopposedestrogenaspartharmone 2. Duringmenopause,theestrogenproducedfrom 1. .Lutealinsufficiency: 2. Anovulation: 1. deficiency. example ofdiseasesecondary toprogesterone (Alzheimer’s disease)maybe,atleast inpart,another healthy. A disordersuchaspremature senility glucose levelsduetoestrogendominance. as itstabilizestheimpairedhomeostaticcontrolof with diabetesandthosereactivehypoglycemia . cell’s uptakeofsodiumandwater, thuspreventing women asitisanaturaldiureticandpreventsthe from supplementationwithnaturalprogesterone. unrecognized estrogendominanceandwillbenefit energy, intolerancetocold,are actually suffering from signs ofhypothyroidism,suchasfatigue,lack cancer. depression, ,breastswelling&endometrial water retention,fibrocysticdiseaseofbreast, significant increaseinbreastcancer(5.4times), replacement therapyhasbeenassociatedwith of progesteroneleadstoestrogendominance. androstenedione toestrogenandabsolutedeficiency of androstenedione.Fatcallsconvert decreasesbutthereisnodrasticreduction with highestrogen. malfunctions. Henceprogesteronelevelsarelow mood swings,breasttenderness,etc. estrogen dominanceleadstosymptomslikePMS, progesterone level. The lackofestrogenwithrelative Laboratory measuresshowbothlowestrogenand formed andthereisnoincreaseinprogesterone. Here theovumisproducedbutcorpuslutem When thereisanovulation,thecorpuslutealnot progestin.( prognostic factorsthatpredictafavorableresponseto estrogen and/orprogesteronereceptorsasimportant histology, longdisease-freeinterval,andexpressionof Nevertheless, moststudiesdosupportlow-grade patients withadvancedorrecurrentendometrialcancer. Progesterone agentshavebeenextensivelyusedin PROGESTERONE TREATMENT: AND Progesteroneisresponsibleforenhancingthelibido. · Progesteroneisessentialforthehealthydevelopment · with betteracceptancerates vaginal bleedingintheinitial monthshasbeenassociated preinsertion counselingregardingtheunscheduled applications beyondcontraceptivecapabilities.Careful has beenanemerging trendwithprovenwiderclinical dominance .Levonorgestrel releasingIntrauterinesystem and treatthesymptomsassociatedwithestrogen routes ofadministrationhavebeenproventoalleviate acceptance ratesoftherapy.Progesteronesinvarious side effects associatedwithithelp inimprovingthe regarding theneedforlongtermmedicationand with estrogendominance.Counselingandawareness with hormonalsupplementationforsymptomsassociated relaxation seemstobethemainstayoftreatmentalong A healthylifestylewithabalancednutritiousdietand CONCLUSION: Consumingofphytoestrogen(soyabean,yams, · Avoiding drinkingfromplasticbottles orStyrofoam o Heatingthefoodinglassorporcelainratherthan o Eatingorganic meatanddairyproducts o LimitingtheexposuretoXenoestrogen · Reducestress · pains. Low progesteronelevelsleadtorecurringachesand of themyelinsheathwhichprotectsnervecells. ESTROGEN DOMINANCE LIFESTYLE MODIFICATION REQUIREDIN from binding. estrogen cellreceptorandpreventsxenoestrogen alfalfa, licorice)canbebeneficialasitbindsto cup. plastic inmicrowave. 9,10) to ? 8 Sushil, 7 LockhatFB,EmemboluJO,KonjeJC. The efficacy, 6 ExpertRevofKivesS,BrownJ,Prentice A, Deary AJ, System (LNGIUS)inMenorrahgia: A Follow-UpStudy. 5 Taru, G., Nupur, G., Sangeeta,G., Pushpa,B.,Jyoti,J. 4 BarringtonJW,Bowen-simpkins P. The Levonorgestrel 3 Wyatt K,DimmockP, JonesP, ObhraiM,O’BrienS. 2. Magor AL .JWW.The premenstrualsyndromeIn 1 Lee. REFERENCES Lesion—An Alternative Intrauterine SystemforMenorrhagiaDuetoBenign 20, 789–793(2005) (levonorgestrel): a3yearfollow-up. with anintra-uterineadministeredprogestogene symptomatic endometriosisundergoing treatment side-effects andcontinuationratesinwomenwith Reviews Ltd Expert Gynecol. 2012;7(2):141-148.©2012 Syst. Rev. associated withendometriosis. Bland E.Progestagensandanti-progestagensforpain 196 Open JournalofObstetricsandGynecology and Sushma,K.(2014)Levonorgestrel Intrauterine IU systeminthemanagementofmenorrhagia review. management ofpremenstrualsyndrome:systematic Efficacy of progesteroneandprogestogensin Livingstone,1984,334-350. gynecology.vol.4Edinburgh:churchil .Studd(ed) Progressinobstetricsand Pub, 1993. Natural progesterone BMJ et al. 2,CD002122(2000).(Obstet 2001; 323:1–8. (2005) Therapeutic UseofLNG The JournalofObstetricsand : 35,Sebastopol,Calif.:BLL Database Hum. Reprod. , 4 , 190- 10 Thigpen JT, BradyMF, Alvarez RD.etal.Oral 9 DecruzeSB,GreenJA.Hormonetherapyinadvanced J ClinOncol1999;17(6):1736-1744 response studybytheGynecologicOncologyGroup. advanced orrecurrentendometrialcarcinoma:adose- medroxyprogesterone acetateinthetreatmentof Int JGynecolCancer2007;17(5):964-978 and recurrentendometrialcancer:asystematicreview. Gynecology ofIndia , 55 , 541-543.

45 FOGSI FOCUS 46 FOGSI FOCUS may beaffected byit. years. Randomcyclesofnormally menstruatingwomen Consistentlyshortlutealphaseduration(lessthan13 • Lowintegratedlutealphaseprogesterone. • Delayinendometrialmaturation morethan2daysin • change ofdefinitionasfollows: dominant follicle. changes oftheendometriumafterovulation concentrations.² Hencethereisinadequatesecretory endometrium tootherwisenormalprogesterone corpus luteumorsuboptimalresponseofthe deficient productionofendogenousprogesteroneby It isdefinedasaconditioninwhichthereeither (LPD) wasfirstdescribedbyGeorgeanna Jonesin1949.¹ LUTEAL PHASEDEFECT women. Numberoffactors likedieting can bemadeonlyafterrepeated testinginnormalfertile detection ofmidcycleLHsurge totheonsetofmenses. days), mostaccuratelydelineatedbytheintervalfrom endometrium. cycle dayinthehistologicaldevelopmentof 2 successiveendometrialbiopsiesbeyondtheactual It affects womenofallracesduringtheirreproductive Since, thentherehasbeenanevidencebased Luteal phaseinsufficiency orLutealphasedeficiency Email id–[email protected] Shimla, HimachalPradesh. Incharge InfertilityClinic MD, MICOG,DHA.MD, 3,4. DrAlok Sharma, 5 Therefore, thediagnosisof LPD 6 , recentchild

refractory toLHactioninlate lutealphase. normal corpusluteumfunction. Corpusluteumbecomes in steroidogenesis.Pulsatile LHactionismandatoryfor the cholesteroltransport,which istheratelimitingstep forms deficientcorpusluteum.STAR proteingoverns formation andfunctionofdominantfollicle. This further abnormal FSH&LHpulsatilityleadtodefect in follicular FSHlevels,alteredFSH/LHratio, 14days. The follicularphaseabnormalitieslikelow endometrium. level ofthehypothalamus/pituitary, theovaryor subsequent toit.Itcanresultfromabnormalitiesatthe function ofcorpusluteumandtheendometrialchanges ranges from3.7%to20%. women withinfertilitythereportedprevalenceofLPD birth pregnancy lossesLPDisreportedin25%to40%cases. and 51%dependingonthediagnosticcriteriaused. patient. The incidenceofLPDisreportedbetween6.6% relevant ifitispresentinmostmenstrualcyclesa affects itsincidenceinnormalwomen.LPDisclinically Pathophysiology Normal lutealphaselengthisrelativelyfixedat12- The pathophysiologyofLPDinvolvesformationand 7 , lactation

8 , extremesofreproductiveage Medical College,Shimla.(HP) KNSH forM&C,IndiraGandhi Dr SandeepSinghRathore 13,14 Inwomenwithrecurrent 7 9,10,11 12 In 15 ,

47 FOGSI FOCUS 48 FOGSI FOCUS not recommendedthesedays. interpret bythepatientand physicianandthereforeis luteal phasechanges. regarding lowerlevelsofprogesteroneneededfornormal between 1ng/mland5ng/ml. There isnoconsensus leutinisation thresholdhasbeensuggestedtopresent occurs leutinisationchangesinendometrium. The gonadotrophin stimulus. progesterone mainlyafterhumanchorionic small cellsarefromthecainternawhichproduce basal progesteroneunderpulsatileLHstimulus,while secreted inapproximately90-minutepulses. increase persistingforatleast 11 days. in bodytemperatureabove thatofprevious6daysand from beginning. BBTcharts 1. and baseduponfollowingphysiologicobservations. completely accurate.Diagnostictestsinfluencedby LPD diagnosisisneitherstraightforwardnor Diagnosis result inLPD. hyperprolactinemia previously variousotherconditionslike hypothyroidism The testsavailabletoassesslutealphasefunctioning FailureofincreaseHCGlevelcausescorpus 5. AfterimplantationtherisinglevelsofHCGaffect 4. Follicularphaseestrogen andlutealphaseestrogen 3. Peaklevelsofprogesteroneisobserved6-8days 2. Durationoflutealphaseis12-14daysnormally 1. In adequatelyestrogen-primedendometriumthere Large cellsdevelopfromgranulosaandproduce Daily progesteroneproductionis25-50mgwhich Ovulation isindicatedby0.2pC(0.5pF)increases The usefulnessofBBTinLPDwasquestionableright In additiontothewellrecognizedassociationsnoted blood, serumandsalivaendometrialsampling. direct testslikeprogesteroneandestrogenlevelin are indirecttestslikeBasalbodytemperatureand luteum failureanddecreaseinprogesteronelevel the progesteronesecretionbycorpusluteum response and progesteronecausecharacteristicendometrial after ovulationanditissecretedinpulses 20 23 , 19 18 , thyroiddisease;inparticular 16,17 21 24 , endometriosis It isdifficult to 22 maturation, toincreaseendometrial receptivityandto evidence. Although itisgiventopromoteendometrial neither justifiednorwarranted asperthepresent hyperprolactinemia. Empirical treatmentofLPDis hypothalamic dysfunction,thyroiddysfunction or the correctionofanyunderlyingconditionlike Treatment ofLutealPhaseDefect enough tomakethediagnosisofLPD. women fromwithLPD(). biopsy isanimprecisetoolfordifferentiating fertile randomized clinicaltrialssuggestedthatendometrial levels mayvaryupto8foldswithin90minutes. levels arenotconstantduetoitspulsatilereleaseand 80%. > 30ng/mlhasasensitivityof100%andspecificity levels takenbetweenday5and9afterovulationof to defineLPD.Itissuggestedthatsumofthreemidluteal random progesteronelevelsisnotavaliddiagnostictest progesterone levelsdefine‘fertile’lutealfunctionso any purposeindiagnosingLPD.Nominimumserum Therefore singlevalueofprogesteronedoesnotserve depicts implantationwindow. placental development.Midlutealendometrialbiopsy phase deficiencyaffects thenormalimplantationorearly because ofanintrinsicendometrialabnormality, luteal inadequate ovarianhormonesecretionorisdelayed and interintra-observervariability. of outphasebiopsy–2daysor3day, itsinterpretation regarding timingofbiopsy, numberofbiopsies, definition test toevaluateLPDbymany. Butthereareconcerns Endometrialbiopsy 3. pregnancy isviableorextrauterine. levels havesomevalueindeterminingwhether is simulatedbyHCGtoproduceprogesteroneandits secreted inpulsatilemannerreflectingLHpulses. early lutealphase.Inmidandlatephaseitis production beginsafterLHsurge andisnonpulsatilein is measurementofSerumprogesteronelevels.Its Progesterone levels 2. infertile women. appearance ofoutphaseendometriuminnormaland is noconsensus. When thereisnodifference insporadic to performendometrialbiopsyintwocycles The firstapproachtotreatmentofpotentialLPDis To summarisenoneoftheavailabletestisgood In theorywhetherthematurationisdelayedby It isconsideredtobethemostimportantdiagnostic Another commonmethodusedfordiagnosisofLPD 27 Once pregnancyisestablished,thecorpusluteum 31 Recentprospective,blinded, 29 The commonpracticeis 28 30 , butthere 25 Its 26 REFERENCES so far. independent entitycausinginfertilityhasnotbeenproven in non-IVFcycleisnotrecommended.LPDasan progesterone levels. function availabletocliniciansisthreepooledmidluteal setting. The bestmeansofestimatinglutealphase This methodisimpractical,however, exceptinaresearch progesterone levelsdailythroughoutthelutealphase. and hasamultifactorialcause SUMMARY beneficial in ART cycles. HCG innaturalorunstimulatedcycles. Though theyare to supportroutinesupplementationwithestrogenand for IVF. They areusefulincontrolledovarianstimulationcycles progesterone isbeneficialinnatural,unstimulatedcycles. suggested byfewstudies. There isnoevidencethat by improvingthequalityandquantityoffolliclehasbeen pregnancy. support implantationanddevelopmentofearly .PirkeKM,SchweigerU,Strowitzki T, et al:Dieting 6. Strott CA, Cargille CM,Ross GT, LipsettMB. The 5. SonntagB,LudwigM. An integratedviewonthe 4. SiktosiGS,BanhidyFG, ACSN. Fundamentalrole 3. HayashiM,SuginamiH, Taii S,Mori T: Endocrine 2. JonesGES:Someneweraspectsofmanagement 1. To concludeatthemomenttestingandtreatingLPD The diagnosisisbestmadebymeasuringserum LPD isasubtledisorderofcorpusluteumfunction Ovulation inducingdrugslikeclomiphenetreatLPD young womenthroughimpairment ofepisodic causes menstrualirregularities innormalweight 246-51 short lutealphase.JClinEndocrinolMetab1970;30: ClinEndocrinol(Oxf). Oct2012;77(4):500-7 luteal phase:diagnosisandtreatmentinsubfertility. Arch GynaecolObstet.Nov2012,286(5):1299-305 of folliculo-lutealfunctioninrecurrentmiscarriage. menstrual cycle.EndocrJ40:297,1993 in theearlyfollicularandmidlutealphasesof assessed byGnRH/TRHstimulationtestsperformed pathophysiology oflutealphasedeficiencyas infertility. JAMA 141:1123, 1949 32,33,34 Similarlythereisnosubstantialevidence 5 Wuttke W, PitzelL,Seidlova-Wuttke D,HinneyB. 15. OliveDL. The prevalenceandepidemiologyofluteal 14. BalaschJ, Vanrell JA.Lutealphasedeficiency:an 13. BroekmansFJ,Knauff EA, Valkenburg Oetal.PCOS 12. ApterD, Vihko R:Earlymenarche,ariskfactorfor 11. LentonEA,LandgrenBM,SextonL:Normal 10. Rosenberg SM,JohnsonM,RiddickDH:Luteal 9. DiazS,CardenasH,Brandeis A, etal:Relative 8. GrayRH,CampbellOM,ZacurHA,etal:Post 7. 8 PracticeCommittee ofthe American Societyfor 18. KiriakidouM,McAllisterJM,Sugawara T, etal. 17. HinneyB,HenzeC,Kuhn W, etal.thecorpusluteum 16. deficiency (LPD). LH pulsesandthecorpusluteum:lutealphase ClinObstet Gynecol phase deficiencyinnormalandinfertilewomen. 371. hormonal stimulation. inadequate endometrialresponsetonormal 113(110):1210-7 and associationwithmetabolicfactors.BJOG2006; change inprevalenceamong WHO IIanovulation according totheRotterdamconsensuscriteria: 1983 cycles. JClinEndocrinolMetabol57:82, , indicatesearlyonsetofovulatory phase. BrJObstetGynaecol91:685,1984 menstrual cycle:Identificationoftheshortluteal variation inthelengthoflutealphase ObstetGynecol 59:89,1982 phase defectasamarkerofimminentovarianfailure. women. FertilSteril 58:498,1992 to thereducedpregnancyrateofbreastfeeding contributions ofanovulationandlutealphasedefect ClinEndocrinolMetabol 64:645,1987 women monitoredbyurinaryassays.J partum returnofovarianactivityinnonbreastfeeding 1989 luteinizing hormonesecretion.FertilSteril 51:263, FertilSteril. 2012;98(5): 1112-7 luteal phasedeficiency: a committeeopinion. Reproductive . The clinicalrelevance of ClinEndocrinolMetabol. 1996;81;4122-8 (StAR) inthehumanovary. J Expression ofsteroidogenicacuteregulatoryprotein ClinEndocrinolMetabol. 1996;81:565 insufficiency: amultifactorialdisease.J VitamHorm . 1991;34:157-166. Intern JFertil . 2001;63:131-158. . 1986;31:368-

49 FOGSI FOCUS 50 FOGSI FOCUS 7 JordanJ,CraigK,CliftonD,etal.Lutealphase 27. 6 Speroff L,FritzMA.ClinicalGynecologic 26. Steele PA, Braund W, JuddSJ.Regulation of 25. Ayres- de-Campos D,Silva-CarvalhoJL,oliviera 24. LentonEA, Weston GA,CookeID.Problemsin b) a)MoghissiKS. Accuracy ofbasalbodytemperature 23. Homburg R, Armar NA,Eshel A, etal.influenceof 22. ShermanBM,KorenmanSG. Measurementof 21. b) DalyDC, Walters CA,Soto-AlborsCE,etal. a) Veldhuis JD, Worgul TJ, MonsaertR,etal. A 20. b) MuhlenstedtD,BohnetHG, HankerJP, etal.Short a)CorenblumB,PairandeauN,Shewchuk AB. 19. 1994;62:54 methods incommonclinicaluse.FertilSteril defect: thesensitivityandspecificityofdiagnostic Lipincott Williams& Wilkins;Philadelphia: 2005 Endocrinologyand Infertility, 7 luteal phase.ClinReprodFertil.1986;4(2):117-24 pulsatile secretionofprogesteroneduringthehuman Reprod. 1995;10(8):2010-6 body temperaturegraphsfrominfertilewomen.Hum C, etal.Inter-observer agreementinanalysisofbasal infertility clinic.BrMedJ.1977;1(6064):803-5 using basalbodytemperaturerecordingsinan 27(12):1415-21 foe ovulationdetection.FertilSteril. 1976; 1988;297(6655):1024-6 polycystic ovarysyndrome.BMJ. ovulation, conceptionandearlypregnancylossin serum luteinizinghormoneconcentrationson 1974;38(1):89-93. luteal phase.JClinEndocrinolMetab. disorders ofthehumanmenstrualcycle:short plasma LH,FSH,estradiolandprogesteronein FertilSteril. 1983;40(3):305-10 defects ispredictiveoftherapeuticoutcome. Endometrial biopsyduringtreatmentoflutealphase human. JEndocrinolInvest.1981;4:31-6 andleutinising-hormonesecretioninthe possible roleofendogenousopiodsinthecontrol 1978;23(3):213-8 luteal phaseandprolactin.IntJFertil. defects. ObstetGynecol.1976;47:486-8 Prolactin hypersecretionandshortlutealphase th edition. 4 PracticeCommitteeof American SocietyFor 34. DayaS,Gunby T. Lutealphasesupportinassisted 33. PrittsEA, Atwood AK. Lutealphasesupportin 32. b) peters A, RileyP, etal.Prevalenceofout-of-phase a)Grunfeldl,SandlerB,etal.Lutealphase 31. OliveDL, ThomfordPJ,et al.twenty-fourhour 30. HuangKE. The primarytreatmentoflutealphase 29. MolBW, LijmerJG,et al. The accuracyofsingle 28. educational bulletin.FertilSteril 2008;89:789-92 pregnancy inthetreatmentofinfertility:an supplementation duringlutealphaseandinearly Reproductive Medicine.Progesterone Reviews 2004;(3):CD004830 reproduction cycles.CochraneDatabaseSystematic trials. HumReprod2002;17:2287-99 infertility treatment:ametaanalysisofrandomized Gynecol. 1992;166:1738 endometrial biopsyspecimens. Am JObstet periovulatory phases.FertilSteril. 1989;52:919 deficiency aftercompletelynormalfollicularand FertilSteril. 1989;51:587-92 with otherindicatorsoflutealphaseinsufficiency. midluteal phaseoftheinfertilepatient:correlation progesterone andleutinisinghormoneprofilesinthe Am JObstetGynaecol.1986;155:824-48 inadequacy: progesteroneversusclomiphenecitrate. Reprod. 1998;13:3220-7 of ectopicpregnancy:ametaanalysis.Human serum progesteronemeasurementinthediagnosis Medicine Committee,FOGSI(2014-16) called asrecurrentpregnancyloss of 20weeksgestationinrespectivepregnancyare Three ormoreabortionsconsecutivelywithintheperiod Recurrent Pregnancy Loss: several decades. pregnancy, andithasbeenusedforthis purposefor Progesterone appearstobenecessarysupportanearly fails toidentifyaspecificcausein50%ofcases. pregnant women,andthestandardinvestigativeprotocol Recurrent miscarriageisknowntoaffect 0.5-2%of Introduction: PROGESTERONE INRPL women with3ormoreunexplainedpregnancylosses. significant decreaseinmiscarriageamongpregnant . Progesteroneproducesasmallbut exogenous progesteroneitmaybepossibletoprevent producing enoughprogesterone,sobyadministering who experiencespontaneousabortionsmaynotbe miscarriage orhabitual . Dr.Ajay Mane–Chairperson-Sexual

It hasbeensuggestedthatsomewomen Dr.Ajay Mane (RPL) orrecurrent 1

2 te ass: Other causes : Immunological causes : : Genetic causes Infectious diseases : Endocrine disorders : Anatomical abnormalities may beseen. In certaincasesmorethanonefactororasinglecause Etiology ofRPL:

(2012-14) surgical equipmentcommittee,FOGSI Chirperson –Food,DrugsandMedico- Dr.Rajendrasing Pardeshi– Dr.Rajendrasinh Pardeshi Idiopathic (Almost10%) Environmental causes Thrombotic disorders APS ismainreason. The incidenceis20-50%. rearrangement. (4). structural chromosome parental balanced associated witha 3.5% to5%ofRPLare to 5%(6) The incidenceof0.5% 20% ofRPL. approximately 17%to It sharesabout to 15%ofcasesRPL. These accountfor10% 8

51 FOGSI FOCUS 52 FOGSI FOCUS pregnancy maintenance. Progesterone isverynecessaryfortheoccurrenceand pregnancy: Progesterone…the hormonefor maintenanceof Role ofprogesterone inrecurrent pregnancy loss: of progesterone. The corpusluteumaswellthetrophoblastissource and inpregnancy. the lutealphaseof normal/routine menstrualcycle Corpus luteumistheonlysourceofprogesteroneduring .Inthemanagementoflutealphasedefect. 2. .Progesterone asan immunomodulatory 1. .Itcausesconversionof TH1 to TH2; asa 4. Progesteroneactsontheendometriumvia 3. .Thepre-ovulatoryincreaseinthesecretionof 2. Progesterone helpstheendometriumfor 1. pregnancy loss Typical patient issubfertileorshowsh/oofrecurrent leading toinfertilityorhabitual . production ofprogesterone fromthecorpusluteum LPD isarecurrentpost–ovulatorydeficiencyinthe effect. and bycontrollingNKactivityexertsananti-abortive metabolism, inducesa Th2 biasedimmuneresponse, interferes witharachidonicacid PIBF byactingonthephospholipase A2 blocking factor(PIBF). mediator proteinnamedtheprogesterone-induced Progesterone bindingresultsinthesynthesisofa delta TCR+ cellsdevelopprogesteronereceptors. Following recognitionofderivedantigensgamma/ in thelymphocytes. induced appearanceofprogesteronebindingsites lymphocytes isduetoactivation- Increased progesteronesensitivityofpregnancy molecule. of NKcellsactivity. blocking factor(PIBF)andperformsreduction response producingprogesteroneinduced specific receptors. stromal cells. causing theproliferationanddifferentiation of the productionofprogesteronetakesplace differentiation ofuterine epithelial cells. Then 17â-estradiol (E process ofimplantation. 5 2 ) promotestheproliferationand 1. Clinical evidences: 4. 3. 2. .Prevention of second trimester loss/preterm 3. .shortenedmenstrualcyclesthatareoften c. lowbodyweight,and/or b. advancedage, a. Clinicalcharacteristicsareindicativeofdeficient ` progestogens toprevent There isnoevidencetosupporttheroutine use of 14651858.CD003511.pub2. Issue 2. Art. No.:CD003511. DOI:10.1002/ Cochrane DatabaseofSystematicReviews2008, is required. efficacy ofprogestogen treatment inaffectedwomen unsufficient statisticalpower, furtherresearch onthe miscarriage. As moststudiesonthistopicare of supplementation inwomensufferingfrom recurrent pregnancy outcomeafterprogestogen have revealed aremarkable improvement in benefit from progestogen treatment,… Somestudies women withidiopathicrecurrent miscarriagemay that inadditiontowomenwithlutealphasedefects, A growing bodyofconsiderable evidenceindicates Best PractResClinObstetGynaecol.2008 3 ormore unexplainedpregnancy losses decrease inmiscarriageamongpregnant womenwith Progesterone produces asmallbutsignificant J FamPract.2005 lymphocytes.….exerts ananti-abortiveeffect. of progesterone bindingsitesinthe lymphocytes isduetoactivation-inducedappearance Increased progesterone sensitivity ofpregnancy Int Immunopharmacol.2001 progesterone isalsorecommendednowadays. till 36weekstheuseofvaginalmicronized In knowncasesofcervicalshorteningfromdiagnosis approved byFDA. progesterone) isnotonlyrecommendedbutalso Role ofinjectableprogesterone(17-á-OH labor. benefit fromprogestogentreatment. women withidiopathicrecurrentmiscarriagemay that inadditiontowomenwithlutealphasedefects, A growingbodyofconsiderableevidenceindicates accompanied bypremenstrualspotting progesterone production: 1 Different formulations indifferent situations: group ofwomen. are currently underwaytoinformtreatment forthis mother orbabyintheavailableevidence.Larger trials groups inratesofadverseeffectssuffered byeither significant difference betweentreatment andcontrol in thetreatment group andthefindingofnostatistically may bewarrantedgiventhereduced ratesofmiscarriage of .Treatment forthesewomen seems tobeevidenceofbenefitinwomenwithahistory miscarriage inearlytomid-pregnancy. However, there 3) 1) 2) 500 mgdeepintramuscularinjection. doses. are available.Dose:200-800mgdailyindivided and intramuscularortransdermalroutes. Progesterone): 17 á-hydroxyprogesteroneisadministeredas250- Dose :10to30mgdaily. Dydrogesterone isadministeredasoraltablets. Nowadays betteroralwatersolublepreparations These canbeadministeredbyoral,vaginal,rectal, Pr Synthetic Pr Natural Pr ogester one derivatives: ogester ogestins: ones (Micronized .Szekeres-BarthoJ,Barakonyi A, ParG, PolgarB, 5. HollyBFord,MDandDannyJ.Schust,MD 4. Fox-LeeL,SchustDJ.Recurrentpregnancyloss.In: 3. PriceM,Kelsberg G, SafranekS,DamitzB.,J 2. Walch KT, HuberJC.Progesteroneforrecurrent 1. References Conclusion: immunomodulatory molecule. 2001 June;1(6):1037-48.Progesteroneasan Palkovics T, SzeredayL.IntImmunopharmacol. www.medreviews,com) and Therapy (Obstetrics&Gynecology on ,Recurrent PregnancyLoss:Etiology, Diagnosis, Wilkins; 2007.pp.1277–1322 Gynecology. Philadelphia: Lippincott Williams & Berek JS,editor. Berek andNovak’s recurrent pregnancyloss? inquiries. What treatmentspreventmiscarriageafter FamPract. 2005Oct;54(10):892,894.Clinical ClinObstetGynaecol. 2008 Apr;22(2):375-89. miscarriage: truthanddeceptions.BestPractRes RCTs arerequired. of insufficient powerofstatistics.Furtherresearch, treatment. However, thestudiessofarconductedare recurrent miscarriagemaybenefitfromprogestogen luteal phasedefects,butalsowomenwithidiopathic Growing evidenceshowsthatnotonlywomenwith pregnancy sincesomanyyears. Progesterone hasbeenusedtosupportearly

53 FOGSI FOCUS 54 FOGSI FOCUS luteum anditssecretions of hCGproducedbytheembryoistomaintaincorpus secretes humanchorionicgonadotrophin(hCG). The role and implantationoccur, thedevelopingblastocyst including progesteroneandestradiol(E2).Ifconception corpus luteum,whichsecretessteroidhormones, a naturalcycleischaracterizedbytheformationof a the onsetofmensestwoweekslater. The lutealphaseof ovulation andeithertheestablishmentofapregnancy or by theplacentathroughoutrestofpregnancy. pregnancy. After that time,progesteronewillbeproduced progesterone whichwilldecreaseaftertenweeksofthe implants intheuterus,ovarywillproduce levels willfallandendometriumsheds.Ifanembryo implant. Ifapregnancydoesnottakeplace,progesterone (endometrium) toallowafertilizedegg(embryo) Progesterone preparestheliningofuterus endometrial receptivity. Progesteronealsopromoteslocal after adequateestrogenpriming, progesteroneimproves endometrium inthelutealphase. Byinducingthischange Progesterone inducesasecretory transformationofthe (IVF) CYCLES DURING INVITROFERTILIZATION PROGESTERONE SUPPLEMENTATION Lutealphaseisdeûnedastheperiodbetween Progesteroneisahormoneproducedbytheovary. The role ofprogesterone inthe luteal phase: 1 . (OR) mightdiminishthe mostimportantsourceof quantities ofgranulosacells duringtheoocyteretrieval cycles: The causeofthelutealphase defectinstimulatedIVF by externaladministrationofprogesterone be maintainedevenafterremovalofthecorpusluteum pregnancy loss. They alsofoundthat pregnancycould corpus luteumpriorto7weeksofgestationled to by Csapoetal.Intheirinitialstudy, theremovalof during thefirstweeksofapregnancywasdemonstrated progesterone inIVF. The importanceofprogesterone concentrations wasdetectedunderliningthebenefits of uterine contractilityfrequencyandprogesterone out oftheuterinecavity. A negativecorrelationbetween hindered transferoutcome,possiblybyexpellingembryos uterine contractilityonthedayofembryotransfer Exchange CommitteeChairperson FOGSI International Academic CIMAR FertilityCenter, Cochin Consultant &IVFCoordinator Dr FessyLouisT 2 study ofIVFembryotransferoutcomesbyFanchinetal relaxing propertiesofprogesteroneweresupportedbya for thelowimplantationratesinIVF. The uterine- endometrial receptivityisconsideredlargely responsible inducing nitricoxidesynthesisinthedecidua.Decreased vasodilatation anduterinemusculaturequiescenceby . This studyresultsindicatedthatahighfrequencyof Initially, itwasthoughtthattheremovaloflarge

3 .

9

55 FOGSI FOCUS 56 FOGSI FOCUS tortuous andsecretory there isanincreaseinstromal Progesterone: LH productionviaashort-loopfeedbackmechanism potentially causealutealphasedefectbysuppressingthe oocyte maturationinstimulatedIVFcyclescould also suggestedthatthehCGadministeredforfinal corpus luteum,wouldcausealutealphasedefect.Itwas rise instimulatedcyclesresultinglackofsupportthe co-treatmentdesignedtopreventspontaneousLH agonist the prolongedpituitaryrecoverythatfollowedGnRH shortened thelutealphase. Another theorysuggestedthat diminished thelutealphasesteroidsecretionnor a preovulatoryoocyteinnaturalcycleneither disproved whenitwasestablishedthattheaspirationof defect ofthelutealphase.However, thishypothesiswas progesterone synthesisbythecorporalutea,leadingtoa route progesteroneshouldbegiven stimulation inthelongprotocol. The questionis,bywhat the firstchoiceforlutealphasesupportfollowingovarian increased OHSSriskwithhCG, progesteroneshouldbe to thesameefficacy ofhCGandprogesterone,butthe E2>2700 pg/mlandifthenumberoffolliclesis10.Due OHSS. LutealsupportwithhCGshouldbeavoided if progesterone. HCG isassociatedwithagreaterriskof support withhCGissuperiortothatprovided by to datewhichhasbeenableshowthatlutealphase dose (1000,2500or5000IU). There hasbeennostudy days, every3varyingintervals)orthetotaldaily no rationalebehindeitherthedosefrequency(every2 use ofhCGinlutealphasesupport,thereappearstobe cycles. Despitethevarietyofprotocolsthatexistfor rescuing thefailingcorporaluteainstimulatedIVF an increaseinE2andprogesteroneconcentrations,thus indirect formoflutealsupport.Itisknowntogenerate 1980s. Bystimulatingthecorporalutea,hCGisan become thestandardcareforlutealsupportsincelate rescued bytheadministrationofhCG, thistreatmenthas Human chorionicGonadotropin: needs furtherstudies. debated andthefinalsituationinlutealphasesupport of estradioltoprogesteronelutealsupportiscurrently gonadotrophin (hCG)canbeadministered. The addition ICSI cycles,progesteroneand/orhumanchorionic Options oflutealsupportin ART:

Since itwasfoundthatthecorpusluteumcanbe To correct the lutealphasedefectinstimulatedIVF/ In responsetoprogesterone, theglandsbecome 5 . 4 . vaginal micronizedprogesterone compared withpatientstreatedIMinjectionsor been treatedwithoralmicronizedprogesteronewhen patients withprematureovarianfailure(POF)whohad the secretorytransformationofendometriumin cited studiesdidnotcomment onsedativeeffects oforal routes hadmoreorlesscomparable cycleoutcomethe similar ratesofsuccessful . Although both 1980s luteal supportinIVFwithpoorresultsuntiltheendof Oral progesterone: stimulated IVFcycles (DG) wasintroducedtosupportthelutealphase of bioavailibility. To overcomethisproblem,dydrogesterone suggested thatoraladministrationreducedthehormone’s IVF DG withvaginalmicronized progesteroneasLPSafter that comparedtheefficacy, safetyandtolerabilityoforal undertook aprospective,randomizedstudy(n=430) secretory transformation.Chakravartyetalin2005 effect ontheendometrium,achieving desired metabolite ofprogesteroneandhasananti-estrogenic good oralbioavailability, isabiologically active orally administeredprogesterone progesterone overcomesthemetabolicconsequencesof Parenteral administration(vaginal,rectalandIM)of degradation toits5a-and5b-reducedmetabolites. This metabolicactivityresultsinprogesterone subjected tofirstpassprehepaticandhepaticmetabolism. intramuscular. Progesteroneadministeredorallyis progesterone includeoral,vaginal,rectaland endometrium. Currentlyavailableformulationsof than thederivativesininducingsecretorychangesat lipoproteins, noteratogeniceffects andismoreeffective progesterone hasnoadverseeffects onhigh-density that limitstheiruseduringfertilecycles.Natural lipoproteins, luteolysisandapossiblyteratogeniceffect depression, virilization,decreaseinhigh-density effects andhavebeenassociatedwithmoodchanges, given orally, buthaveahighincidenceofsecondary synthetic derivativesresistenzymaticdegradationif nortestosterone derivatives. The 19-nortestosterone 17-hydroxyprogesterone derivativesand2)19- preparations. Syntheticderivativesorprogestinsare1) into twogroups:naturalprogesteroneandsynthetic implantation. Progesteronepreparationscanbedivided morphologically andfunctionallywellpreparedfor vascularity, thusmakingtheendometriumboth Oralmicronizedprogesteronewasusedfor 10 . BothDGandprogesterone wereassociatedwith 7 . Devroeyetal.in1989reportedanabsenceof 9 . DG, aretroprogesteronewith 6 . 8 . This finding . This which areassociatedwitha highnumberofsideeffects. a viablealternativetotheIM injectionsofprogesterone meta-analysis, vaginaladministrationofprogesterone is used. DespitetheconclusionofPrittsand Atwood’s were significantlyhigherwhenIMprogesteronewas progesterone phase ofstimulatedIVFcyclestreatedwith50mgIM Leeton etal.firstdemonstratedtheextensionofluteal as aninjectionofnaturalprogesteroneinoilIn1985, sustained absorptionandreducedperinealirritation. adheres tothevaginalepithelium,thusfacilitating secretions anddisintegrateintoanadhesivepowderthat pessaries andvaginalgel. The tabletsabsorbthevaginal administration, e.g.vaginaltabletsorcapsules, been incorporatedindifferent formsforvaginal liver metabolizationisabsent.Naturalprogesteronehas vessels andduetotheuterinefirstpasseffect, where progesterone transportbetweenanatomicallycloseblood observed, duetocounter-current exchangein concentrations withlowperipheralserumvaluesare administration ofprogesterone,highuterineprogesterone comfort andeffectiveness a firstchoicelutealsupportregimen,mainlyduetopatient supplementation inIVFhasgainedwideapplicationas Vaginal progesterone: micronized progesterone. synthetic dydrogesteronecomparedwithvaginal vaginal application comparing IMadministrationofprogesteronewith Atwood includedfiveprospectiverandomizedtrails PR A meta-analysispublishedin2002 byPrittsand it wasfoundtohavecomparableclinicalandongoing PR inIVFcyclesinvolvingvaginalandIMprogesterone centers, byLevineevaluatedtheclinicalandongoing also causeinflammatoryreactionsandabscesses. In additiontothis,injectionsofprogesteroneinoilcan causing alackofenthusiasmforthistreatmentmodality. side effects, includingpainfulinjectionsandarash of administrationisoftenassociatedwithanumber significant difference concerningtheoutcome. This route LPS varybetween25and100mg/daywithoutany IM progesterone: Intramuscular progesterone,supplementationisgiven The intravaginalrouteofprogesterone Inanopen-labeltrialin1184 women from16US 12 . The dosesofIMprogesterone usedfor 13 .ClinicalPRanddeliveryrate 11 . Followingintravaginal forms concentration duringthefirst8htwiceashighother of administration,rectalapplicationresultedinserum menstruating women. When comparedwithothermodes during thefollicularphaseofagroupnormally ( andtablet),vaginallyrectally(suppositories) single bolusof50–200mggivensublingually, orally sequential serumprogesteroneconcentrationsaftera bioavailability ofmicronizedprogesteronebymeasuring ICSI. In1987ChakmakijanandZachariahstudiedthe use ofnaturalprogesteroneinwomenundergoing IVF/ Rectal progesterone: luteal phasesupportinthecourseofIVFtreatment seems tobeatleastaseffective as600mgcapsulesfor studies haveshownthat90mgadministeredoncedaily specially developedforvaginaladministration. Various natural progesterone,isavailableinanapplicator pharmacokinetic propertiestoprogesteronecapsules. the majorityofwhichappeartohaveequivalent three timesaday. therefore requirescapsulestobeadministeredtwiceor natural progesteronepercapsulecanbeused. currently availablethatcanbeadministeredvaginally. for vaginaladministration: Comparison ofdifferent progesterone preparations progesterone aslutealsupport instimulatedcyclesiswell corpus luteumareprogesterone andE2. The roleof Progesterone withE2: with micronizedprogesteronefromthedepotoilyphase Replenishment ofthehormoneinaqueousphase is progesterone directlyfromtheaqueousphase. in-water emulsionguaranteesthecontinuousrelease of preparation adherestothevaginalepithelium,oil- base. While thepolycarbophilensuresthat the latterisanoil-in-wateremulsiononapolycarbophil or suppositoriesand8%vaginal The essentialdifference between progesteronecapsules 15 . A numberofpublicationshaveevaluatedtherectal 8% vaginalgelapreparationthatcontains90mg A varietyofprogesteronepessariesarealsoavailable, The doseusedinmoststudiesis600mg/day, which Progesterone capsulescontaining100/200/300mg A limitednumberofprogesteronepreparationsare The twomostimportanthormonesproducedby the gel isthattheformercontainsanoilemulsion,while 6 . 14 .

57 FOGSI FOCUS 58 FOGSI FOCUS amount ofprogesterone increases, thecorpusluteumsecretesanappropriate production. As soonasendogenoushCGproduction administered hCGandtheincreaseinendogenous only ‘fillinthegap’betweenclearanceofexogenously Duration ofLutealSupport: of OR). as thedayofembryotransfer(if3following treating thepatientswithprogesteroneatleastasearly progesterone inaccount,itisrecommendedtostart days. However, takingtheuterolytic effect of maturation coversthelutealphaseforamaximumof8 after OR. The HCGadministeredforfinaloocyte that thetimingofLPSshouldnotbelaterthanday3 the LPS.Referringtopublisheddata,itisevident studies areneededtoestablishbesttimingofonset after OR compared withpatientswhobeganlutealsupport3days days afterORresultedinadecreasedPRof24%when days. Inonestudyby Williams etal,delayingLPSuntil6 clinical practiceinvolvesbeginningLPSondifferent The onsetofLutealPhaseSupport: vs. highresponderandlowresponders. support inlongagonistvs.antagonist,normalresponder studies areneededtoclarifytheexactroleofE2luteal has nobeneficialeffects onpregnancyrates progesterone forlutealphasesupportinIVF/ICSIcycles analyses hasshownthattheadditionofE2to in stimulatedIVFcyclesmaybebeneficial. Two meta- demonstrated whetheradditionalsupplementationofE2 established. However, ithasnotyetbeenclearly luteal phasesupportwithprogesterone; optimize theresultsoftreatment stimulation Summary: progesterone supplementationduringearlypregnancy or contestthegenerallyacceptedpracticeofprolonging . There werenostudiestoeithersupport extend lutealsupportforvaryingdurationsafterpositive OR comparedwithstartingatembryotransfer no difference hasbeenfoundwhenLPSwasstartedat Theoretically, progesteronewouldbeofbenefitto Timing ofLPSremainsthesubjectdebate.Current — Lutealphasesupportwith hCGisnotsuperiorto —in principle,lutealphase supportisnecessaryto In lutealphasesupportinIVFfollowingovarian 17 . Where asinanotherstudy byBaruffi etal 19 . HowevermostIVFcenters 18 16 .Further, . Further . 5 4 3 2 1 References eliminating thecurrentlutealphasedefect with thesignificantfringebenefitofreducingor into amorephysiologicalprocess,milderstimulation, rates. Inthecomingyears,IVFstimulationmayevolve assisted reproductionresultsinanincreasedPregnancy progesterone administration. there isnoreasontoexpectadisadvantagewithvaginal direct comparisonofi.m.withvaginalprogesterone,but metabolites; increased rateofside-effects duetounphysiological i.m. orvaginaladministration,andisassociatedwithan controversial natureofthedataavailable; definitive conclusioncannotbedrawnduetothe phase supportisprobablynotworthwhile,althougha complications; progesterone, ofOHSSanditscorrespondingpotential risk, ascomparedwithlutealphasesupport advantage whenprogesteroneisadministered; Fanchin R,RighiniC,OlivennesF, Taylor S,deZiegler Csapo AI, PulkkinenMO,RuttnerB,Sauvage JP, Wiest FatemiHM The lutealphaseafter3decadesofIVF Soliman S,DayaCollinsJ,HughesEG. The roleof LutealPhaseSupportwithHCGorprogesteroneafter — At present, insufficient dataareavailablefora — The useoforalprogesteroneisclearlyinferiorto —the administrationofestradioltosupplementluteal — LutealphasesupportwithhCGbringsanincreased — SupplementaryadministrationofhCGbringsno Van Steirteghem AC, SmitzJ,CamusM, Van procedures. HumReprod1988; 3:161–4. phase after Waesberghe L,DeschachtJ,KhanIetal. The luteal 1068–76 analysis ofrandomizedtrials.FertilSteril 1994;61: luteal phasesupportininfertilitytreatment:ameta- J ObstetGynecol1972;112:1061–1067. in pregnancymaintenance.I.Preliminarystudies. Am WG. The significanceof the humancorpusluteum fertilization. HumReprod1998;13:1968–1974. embryo transferalterpregnancyratesafterin-vitro D, FrydmanR.Uterinecontractionsatthetimeof ReproductiveBioMedicineOnline,2009,:19,S4,1–13 in-vitro fertilization andrelated 12 11 15 14 13 10 9 8 7 6 Belaisch-AllartJ, Testart J,FriesN,FormanRG, Buvat J,MarcolinG, GuittardC,DehaeneJL,Herbaut ChakravartyBN,ShirazeeHH,DamP, GoswamiSK, Devroey P, PalermoG, Bourgain C, Van Waesberghe LeetonJ, Trounson A, JessupD.Supportoftheluteal Simunic V, Tomic V, Tomic J,NizicD.Comparative PrittsEA, Atwood AK. Lutealphasesupportin Strehler E, Abt M,el-DanasouriI,Sterzik K. Cicinelli E,SchonauerLM,GalantinoP, MatteoMG, Chakmakjian ZH,ZachariahNY. Bioavailabilityof 2000;15(Suppl 1):159–165. specificity ofvaginalprogesterone.HumReprod Cassetta R,Pinto V. Mechanismsofuterine Biochem MolBiol2005;97:416–420. cycles: resultsofarandomisedstudy. JSteroid support inassistedreproductivetechnology(ART) intravaginal micronisedprogesteroneaslutealphase Chatterjee R,GhoshS.Oraldydrogesteroneversus on IVF cycles.In: Abstract book.11th World Congress application intheefficacy oflutealphasesupportin progesterone doesnotdiffer toprogesteronegel Transvaginal administrationofmicronized Fertil Steril 2007;87:83–87 Utrogestan capsules,usedforlutealphasesupport. progesterone formulations,Crinone8%geland study oftheefficacy andtolerabilityoftwovaginal randomized trials.HumReprod2002;17:2287–2299. infertility treatment:ameta-analysisofthe Fert Embryo Transf 1985;2:166–169. controlled trialwithintramuscularproluton.JIn Vitro phase invitrofertilizationprograms:resultsofa 1987;2:183–185. supplementation inanIVFprogramme.HumReprod Frydman R. The effect ofdydrogesterone 287. Genetics, 9–14May1999, Sydney, Australia, 1999; Fertil 1989;34:188–193. administration inpatientswithabsentovaries.IntJ L, SmitzJ, Van Steirteghem AC. Progesterone with oralprogesterone.PresseMed1990;19:527 Superiority ofvaginalprogesteroneincomparison of anLHRHanalogforinvitrofertilization. JC, Louvet AL. Lutealsupportafteradministration J ReprodMed1987;32:443–448. progesterone withdifferent modesofadministration. Fertilization andHumanReproductive . 19 18 17 16 SchmidtKL,ZiebeS,PopovicB,Lindhard A, Loft Baruffi R,Mauri AL, PetersenCG, Felipe V, Franco SmitzJ,Bourgain C, Van Waesberghe L,CamusM, Williams SG, OehningerS,Gibbons WE, etal. 2001;75:337–341. no effect onthedeliveryrate.FertilSteril during earlygestationafterinvitrofertilizationhas A, Andersen AN. Progesteronesupplementation rates. J Assist ReprodGenet2003;20:517–520. starting onthedayofoocyteretrievalpregnancy JG, Jr. Effects ofvaginalprogesteroneadministration study. FertilSteril 2001;76:1140–3. after invitrofertilization:arandomizedprospective supplementation resultsindecreasedpregnancyrates Delaying theinitiationofprogesterone induced superovulation.HumReprod1993;8:40–45. micronized progesteroneinbuserelinandHMG supplementation inadditiontointravaginal randomized studyonoestradiolvalerate Devroey P, Van Steirteghem AC. A prospective

59 FOGSI FOCUS 60 FOGSI FOCUS ENDOMETRIOSIS PROGESTINS IN have onlybeenpartlyunderstood, eventhoughtheyhave morphological changesinduced byprogestinsinhumans The detailsofthemechanisms ofactionandthe Mechanism ofaction processes, breasttissueandgenitalorgans. of actiononthehypothalamic–pituitaryaxis,metabolic with respecttotheirpharmacologicalprofileandpotency for example)havebeenusedintreatment. They differ (norethisterone, ,desogestrelanddienogest, dydrogesterone) orderivativesofC19-nortestosterone progesterone (medroxyprogesteroneacetate[MPA] and the treatmentofendometriosis.Different derivativesof component havebeendemonstratedtobeeffective in For over40years,oralprogestinslackinganestrogen Progestins costs ofadrugarerelevant. is oftennecessary. Therefore, theefficacy, tolerabilityand combination ofboth.Long-termorrepeatedmedication Treatment requiresamedicalapproach,surgery ora the qualityoflifeinwomensuffering fromthisdisorder. a varietyofsymptomsandmanifestationsreduces Endometriosis isachronicdebilitatingdiseasethathas Introduction Nirmiti FertilityandIVF, 1 MGRoad, Thane West 400602. 0225035095, +919820066010 Near NaupadaPoliceStation, Dr PratikTambe MDFICOG, [email protected] Parasmani, st Floor, cast doubtoverthishypothesis. decidual transformationand atrophy. Laterstudieshave secretory changesinectopic lesionswerefollowedby as knownfromtheuterine mucosa,meaningthat postulated activitiesviathesteroidreceptormechanism a contentiousissue.Earlierstudiesonthesubject The modeofactionontheendometrioticimplantisstill on TargetEffects Tissue breakthrough bleedingisacommonoccurrence. therapy resultsinlowserumestradiollevels, of theeutopicendometrium. As continuousprogestin hypergestagenic statuscausesdecidualtransformation of ovariansteroids. The hypoestrogenicand steroidogenesis withanovulationandlowserumlevels application leadstoasuppressionofovarian reduction inFSHandLHsecretion. Their continuous amplitude ofpulsatileGnRHrelease,resultingina Progestins reducethefrequencyandincrease differ amongstthedifferent derivatives. uterine endometrium. The doses requiredtoachievethis effect isviasecretorytransformationofestrogen-primed different countriesforanumberofyears. The therapeutic been usedinthetreatmentofendometriosismany MG Road, Thane West 400602. Station, Parasmani, NearNaupadaPolice Nirmiti FertilityandIVF, 1 Dr LataRajputMD 10 st Floor, 1

61 FOGSI FOCUS 62 FOGSI FOCUS reaction andnecrosiscouldnotbedemonstrated. some hadabortivesecretoryreactions,butdecidual however, somedemonstratedarrestedepitheliumand progestin influence,someimplantsremainedunchanged; of endometriosis:afterlong-termuse(9months) Morphological studieshaverevealeddifferent reactions sensitivity oftheimplantsduringlong-termtreatment. reduce thesynthesisofreceptors,resultingindiminished increased proliferation,asestradiolisnotinactivated. and cannotbeactivatedbyprogestins,resultingin 17-â-hydroxysteroid-dehydrogenase type2isdefective addition toloworreducedreceptorconcentrations. The eutopic andectopicendometrialtissue. absent receptors inverylowconcentrations,orelsetheyare 60 Improvement insubjectivecomplaintsvariesbetween vary littlefromestrogen–progestincombinationtherapy. reported inmainlyretrospectivestudies. These results doses (5–20mg/day)hasawiderangeofdifferent results Clinical Experience and progressionofendometrioticimplants. microvessel density, whichcanreducethedevelopment structural changesinthemicrovesselsanddecreased angiogenesis intheectopicendometriumthrough at C17andadoublebondbetweenC-9C-10,inhibits endometrium. involved intheimplantationandprogressionofectopic suppression ofmatrixmetalloproteinases,whichare found toreduce TNF-á activation.Progestinsalsoinduce endometriotic stromalcells,whereasprogestogenswere the lutealphase. endometriotic fociaredelayedandstillproliferativein the G0/G1phaseofcellcycle. cells dienogest caninhibitproliferationofendometrialstromal caused byspecificchangesinenzymesystems, progestins- knownasprogesteroneblockage-maybe interruption ofthemedication for5–7days. increasing dosages,additional estrogenmedicationor bleeding problems,which havetobetreatedthrough induced sideeffects. The disadvantagesarespotting and contraceptives relateto the avoidanceofestrogen- 10 Endometriotic focieithercontainprogesterone Oral administrationofdifferent progestinsatlow Dienogest, aC19steroidwithcyanomethylgroup TNF-á andestradiolinduceproliferationof On comparativeultrastructuralexaminations, and 94% in vitro 2 , and enzymesystemsdiffer widelybetween due toanincreaseinthearrestofcells 11 . The advantages ofprogestinsoveroral 5 This insensitivitytotheinfluenceof 9 8 Furthermore, 3 Progestins 4

6 in 7

partial regressionwithscarformation. was a50%regressionrateofectopicimplantsand13% least 6monthsaftercessationoftherapy. useandthedecreaseinpainpersistedforat in symptomsandbleedingirregularitiesduring safety andefficacy profile,withaprogressivedecrease depot estrogen andcyproteroneacetate(CPA) (NETA) versusacombinationof prospective randomizedcontrolledtrialusing possible totreatwithprogestinssymptomatically. Ina as well after diagnosisofendometriosisorsurgical excision with MPA wasaseffective asdanazol,usingmedication women of lifeandpsychiatricprofilesignificantlyintreated monotherapy for6monthsversusOCsimprovedquality reduced significantlywithbothtreatmentregimens.CPA pelvic pain,deepdyspareuniaanddysmenorrheawere tested dienogest2mgdailyagainstplacebo Pain Endometriosis Associated and highbioavailability. action ontheendometriuminlowdoses,ashorthalf-life characteristics of19-norprogestins:strongsuppressive antigonadotropic activity, combinedwithtypical tolerability, antiandrogenicactionandweak 2 mg/day. Ithastypicalprogestogenicproperties:good to albuminanddoesnotaccumulateusingoraldosesof -bindingglobulin,isboundunspecifically guidelines and a6-monthfollow-up enrolled inalong-termtreatmentstudy(upto53weeks) abovementioned study, thewomen(n=168)were months ofmedication. After finishingthe of treatment,andwerereducedduringthefollowing occurred inupto80%ofpatientswithinthefirst3months Bleeding problemswerethemainsideeffects and improvement inendometriosis-relatedsymptoms. symptoms duringand1year aftertreatment,butno progestins, thereissignificant reductionofpain doses of4and6mg/day which persistedin60%ofwomen,evenwithincreased pain. However, in95%ofcasesspottingwasreported, In aprospective,randomizedtrialwithMPA, there Two recentpublishedprospectiverandomizedstudies In deep-infiltratingrectovaginalendometriosis,the When comparingGnRHanalogues withlow-dose Dienogest 2mgdaily, reducesendometriosis-related 17 20 . . 18 recommend completeexcision,butitisalso 14 , andshowedasignificant 12 15 . Dienogest doesnotreduce . The drugshowedagood 16 Pain reduction Pain 19 , dyschezia, 13 or versus almost two-thirdsoftreated women. for MPA spotting, bloating andweightgainoccurredin and and sweatingwerethemain problemsinupto59%; for lynestrenol,hotflushes, to athirdofthepatients; bloating, weightgainand headache wasreportedinup medication. are furthercausesforthecessationoflong-term in C17-derivatives. Weight gainandbleedingproblems influences onmoodswingsanddepression,moreseen system, moreseeninC19-derivatives,aswellnegative of lipidandcarbohydratemetabolismtheclotting Side Effects examination inseveralofthestudies. These findingsweresupportedbylaparoscopic significant reductioninthenumber/severityofsymptoms. of womenbecamesymptom-freeorexperienceda of dayspercycleoverperiods3–9months,themajority in dosesbetween10and60mg/day, forvarious numbers androgenic sideeffects andiswelltolerated. When used of bleedingproblems.Itcanbeusedcyclically, hasno used forsymptomatictreatmentofpainandreduction publications areobservationalorretrospectivestudies they weresurgically correctedornot. All these depending onthestageofendometriosisandwhether norethisterone acetateregimensvaryfrom5to90% Infertility with themedicationofdanazolorGnRHanalogues. relief usingadequatedosagesofprogestinsisidentical effects onthedifferent typesofendometrioticfoci.Pain or repeatedmedication. but progestinsarealsoveryusefulforlong-termtreatment Primarily, amedicationwithGnRHagonistsisindicated, pain anddyspareuniadidnotdiffer significantly. group. The improvementofsymptomslikechronicpelvic reduction ofendometrioticimplantsintheleuprorelin laparoscopy, thereissignificantlymorepronounced in bothgroups;goserelinissuperiortoOCs. At repeat significant reductionofdeepdyspareuniaandcyclicpain medication. an improvementinfertilityafteranyprogestin . There isnorandomizedcontrolledtrialthathasproven differences betweenthemedicationsused For levonorgestrel, spotting,breakthroughbleeding, Negative sideeffects ofprogestinsaredisturbances Pregnancy ratesfollowingMPA, lynestrenolor In conclusion,different progestinshavedifferent Dydrogesterone 24 does notinhibitovulationitcanbe 25,26 For dienogest, For 21 . There isa 22,23 continuation rateof56%forthelevonorgestrel therapy. that deepinfiltratinglesionsarenotresponsivetomedical sonography. This isincontrast to thegeneralopinion nodules wasreduced,asdemonstratedwithtransrectal bowel symptomswerealleviatedandthesizeof andfatiguearereportedbetween1038%. acne, hotflushes,headache,breasttenderness,lossof which wasintroducedintheEuropeanmarketlastyear, common, butbytheendof thestudy70%ofwomen bleeding duringtheinitial monthsafterapplicationis of thelocaladministration oflevonorgestrel. Irregular other prospectiverandomized studieshavebeeninfavor whereas was higherinpatientsreceivingGnRHanalogs, deep infiltratingendometriosisalso. are positiveeffects onendometriosis-relatedpainand with arateof20µg/dayduringperiod5years. There levonorgestrel isdelivereddirectlyintheuterinecavity symptomatic endometriosis. The C19progestogen of progestogens,whichcanbeaneffective treatmentof treatments, anewaspectistheintrauterineadministration group. more bleedingproblemswereobservedintheMPA with low-dosedanazol(50mg/daily),butsignificantly was aseffective asacombinationoforalcontraceptive The injectabledepotMPAwho donotdesirepregnancy. of applicationisrecommendedonlyinelderlypatients, ovulatory cyclesafterdiscontinuance. Therefore, thistype the possibleprolongedintervaltoresumptionof significant drawbacktotheuseofdepotpreparationsis suppressing endometriosis-relatedcomplaints. A Alternative Routes lasting longerthan6–12months. no dataarecurrentlyavailableforprogestintherapy cysts. Therefore, long-termmedicationisrequired,but and medicaltreatmentwillnoteradicatetheimplantsor above 50%ingeneral.Endometriosisisachronicdisease of treatment.Long-termfollow-upshowsrecurrencerates of recurrencesymptomsinthefirstyearafterend progestin medication. They reportedarelativelyhighrate concerning therecurrenceratesaftercessationof Recurrence Rate A 3-yearfollow-upstudyfoundapain-free To reducetheadversesideeffects ofmedical Depot injectionsofMPA areveryeffective in Only afewfollow-upstudieshavebeenpublished 30 . However, reductionofsymptoms 28,29 The painand 27

63 FOGSI FOCUS 64 FOGSI FOCUS 2. Kauppila A, Rönnberg L, ViehkoR. L, Rönnberg KauppilaA, 2. .Obolensky W, KamberJ. Therapie der 4. Vierikko P, Kauppila A, Rönnberg L, Viehko R. 3. implants ofMPA endometriosis isthedevelopmentofsubcutaneous users becameamenorrheicinashortertime. were amenorrheic.Incomparison,allGnRHanalogue .HammondCB,Haney AF. Conservativetreatmentof 1. References GnRH analogueshavetheirplaceinspecialindications. medical treatmentofendometriosisingeneral,whereas with pain-relievingstrategiesareveryimportantforthe the next5–10years,progestinsaloneorincombination but theiruseinhumansisfarfrombeingachieved.For Results inlaboratoryoranimalstudiesarepromising, immunomodulatory substanceslike TNF-á inhibitors. factors, matrixmetalloproteinaseinhibitorsor pathogenesis –inhibitorsofvascularepithelialgrowth endometriosis aretargeting different stepsinthe under developmentforthemedicaltreatmentof dosages, whichisaneedforthefuture. The newdrugs trials comparingdifferent progestinsanddifferent progestins havefoundexcellentapplication. clinically unimportantandtheyareinexpensive, effects areoftentolerable,metabolicdisturbances or repeatedmedicationsareneeded.Sincetheirside endometriosis isachronicdisease,long-termmedications are used,progestinseffective treatment.Because the cycleandstoppinggrowthofendometrium Conclusions the MPA group. agonist groupandbleedingproblemswerefrequentin sideeffects werefoundintheGnRH symptoms, butdemineralizationofboneand no differences wereobservedinthereductionofpain A newapproachtoimprovetheuseofprogestinsin There isalackofsufficient prospectiverandomized It isclearthatifsufficient dosagesforsuppressionof endometrischem. Steroidrezeptoren in Steril. Steroidal regulationofendometriosistissue. (1986). endometriosis. 43, 218–223(1985). 32 31 . When comparedtoGnRHanalogues, Fertil. Steril. GewebeEndometriose 30, 497–509(1978). 33,34 4, 56–59 4, Fertil. 4 Strowitzki T, MarrJ,GerlingerC,Faustmann T,14. Seitz Strowitzki T, Faustmann T,13. GerlingerC,SeitzC. SeligerE,KaltwasserP, SchneiderF,12. RotheK,Röpke .KatayamaH, T, UematsuK 8. AttarE,BulunSE. Aromatase andothersteroidogenic 7. .ZeitounKM, Takayama K,SasanoH 6. SchweppeK-W. 5. 1 AndrewsMC, Andrews WC, Strauss AF.11. Effects of Timmonen S,JohanssonCJ.Endometriosistreated 10. FuL,Osuga Y, MorimotoC 9. trial. week, randomized,multicentre, open-label treating thepainfulsymptoms ofendometriosis:a24- C. Dienogestisaseffective asleuprolideacetatein Obst. Gynec. double-blind, placebo-controlledstudy. associated pelvicpain:a12-week,randomized, Dienogest inthetreatmentofendometriosis- 243 (1995). (Ed.), W deGruyterVerlag, ,, 231– Präklinik undKlinikeinesGestagens vergleichendeBindungsstudien. In: Einfluss aufdenRezeptorstatusimEndometriumund F. BehandlungderEndometriosemitDienogest– Reprod. Update. genes inendometriosis:translationalaspects. (1998). estradiol. in endometriosis.Failuretometabolize17â- 17â-hydroxisteroid dehydrogenasetype2expression 150 (1984). endometriose Umsch. endometriosemitdydrogesteron indepotform. J. Obstet.Gynecol. endometriosis: clinicalandmicroscopicstudies. progestin inducedpseudopregnancyon (1968). with lynestrenol. 3), 1344–1347(2008). endometriotic stromalcell. BrdU uptakewithG0/G1arrestincultured model. hemodynamics inaratendometrialautograft of dienogestadministrationonangiogenesisand Hum. Reprod. Hum. Reprod. 30, 558–562(1973). J. Clin.Endocrinol.Metab. 151, 193–198(2010). . Schattauer, Stuttgart Germany, 133– 12, 49–56(2006). Ann. Chir. Gynaecol. Klinik undmorphologieder 78, 776–787(1959). 25, 633–641(2010). 25, 2851–2858(2010). Fertil. Steril. et al. Dienogest inhibits . Teichmann AT 83, 4474–4478 et al. Dienogest – 57, 144–147 et al. 89(Suppl. Deficient Europ. J. Effect Hum. Ther. Am. 16.Kuhl H.Comparativepharmacologyofnewer 16.Kuhl 18.Special InterestGroupforEndometriosisand 18.Special 17.Telimaa S,Rönnberg L,Kauppila A. Placebo PetragliaF, HornungD,SeitzC 15. 3 Vercellini P,23. Trespidi L, Vendola N. A gonadotropin Bergqvist A, Theorell T.22. Changesinqualityoflife FerreroS,CameriniG, SeracchioliR 20. 19. Vercellini P, Pietropaolo G, DeGiorgi O 4 Schweppe K-W. The placeofdydrogesteroneinthe 24. 21.Vercellini P, DeGiorgi O,MosconiP 5 Vercellini P,25. Aimi G, Panazza S, DeGiorgi O,Pesole progestogens. s00404-011-1941-1971 (2011) (Epubaheadofprint). free followup. dienogest treatmentpersistingduringthetreatment- pain inendometrioticwomen:efficacy ofalongterm Reprod. and ManagementofEndometriosis. Endometrium. 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65 FOGSI FOCUS 66 FOGSI FOCUS management. may beanacceptable alternativeforprimary stage 1Alow-gradeuterine tumors, progesteronetherapy complex atypicalhyperplasiaofendometriumorclinical surgical candidates.Inthissubsetofpatients witheither for patientswithmultiplecomorbiditieswhoarepoor prior tocompletingchildbearing. This mayalsobetrue complex atypicalhyperplasiaand/orendometrialcancer acceptable optionforyoungwomendiagnosedwith .Hysterectomymaynotbe an for bothendometrialadenocarinomaandatypical hysterectomy andbilateraloophorectomy.Thisistrue neoplasia issurgery, includingtotalabdominal in womenwherepreservationoftheuterusisconcern. endometrial cancerandinearlycarcinoma endometrial hyperplasiawhichisaforerunnerof discussion becomesskewed. of progesteroneandcancersisthesubjectarena pregnancy relatedcomplications. When theassociation in maintenanceofpregnancyandaspectrum IN ROLE OFPROGESTERONE The treatmentforpatientsdiagnosedwithendometrial Progesterone mainlyhasaroleinthetreatmentof Progesterone isahormoneuniquelyknownforitsrole of progestintherapybeforeassessingforaresponse. most recognizetheneedforaminimumofthreemonths as earlytenweeksafterinitiationoftreatment,but Progestin therapyhasanimpactontheendometrialcells effective fortreatmentofendometrialhyperplasia. having hyperplasiawithout atypia. “atypical” endometrialhyperplasia withmost(88of96) Out ofthisgroup,only67% (6of9)patientshad 105) ofpatientshadhistologic regressionafter2years. intrauterine device(LNG-IUD). A reported 90%(94of hyperplasia weretreatedwithalevonorgestrel Kingdom ( months. for 12to14dayseachmonth,whentreated3 6 either medroxyprogesteroneacetate(MPA), 10mgdaily endometrium in80to90%ofpatientswhentreatedwith regression ofhyperplasiawithoutatypiatonormal presence orabsenceofatypia.Studies have shown for treatingendometrialhyperplasiavarydepending on endometrial lining. The dosesandtypesofprogestins stromal decidualizationandsubsequentthinningofthe thought tooccurthroughactivationofPRs,resultingin Reversal ofendometrialhyperplasiabyprogestinsis Progestin Therapy inEndometrialHyperplasia Consistently, studies haveshownthatprogestinsare 3-6 Inalarger prospectivestudyfromtheUnited Medical CollegeKolkata Associate ProfessorG&O, Dr.SebantiGoswami n =105),patientswithendometrial 7 11 Othersuccessful 1.2

67 FOGSI FOCUS 68 FOGSI FOCUS yielded mixedresults.Montzetal endometrial cancerwithhighsurgical riskfactors have had nochange. clinical response,sevenwithpartialresponseandthree for sixmonths. Twelve (55%)achievedacomplete 26 weeksfollowedbycyclicestrogen-progestintherapy women <40yearsofageweretreatedwithoralMPA for 22 womenwithstage1Aendometrialcarcinomain 11,13 patients) at12months.However, Dharetal a reported(75%)completeresponserate(sixofeight cancer withoutanyevidenceofmyometrialinvasion,with “progestasert” astheIUDinselectedgrade1endometrial and pilotstudies.Ramirezetal in endometrialcancerhavebeenlimitedtocaseseries Cancer Progestin Therapy inPrimaryEndometrial 25- to73-monthfollow-up. multicenter trialwithonlysixrecurrencesfoundwithin response ratewasfoundusingtheMPA regimenina A reported82%complete(14of17)and18%partial daily upto160mgperday, andoralMPA, 600mgdaily. use ofcontinuousoralmegestrolacetate,starting80mg treatments demonstratedforatypicalhyperplasiainclude response timeof12weeks. duration of6monthsandwhodemonstratedanaverage patients wereidentifiedwhotreatedforanaverage endometrial cancertreatedwithhormonaltherapy, 133 January 1966and2007describingpatientswith 46-month follow-up. complete responseratewithnoevidenceofdiseaseat retreated withprogesterone,fiveofsevenhavinga recurred. Sevenofthepatientswithrecurrencewere treatment after12weeks,24%whoinitiallyresponded treated withprogestins. Although 76% respondedto for atotalof62patientswithstage1Aendometrialcancer IUD. histologic regressionat6months whenusingtheLNG- case seriesoffourpatients withonly25%complete responders becauseofthesubstantialraterecurrence. emphasize theneedforclosefollow-upevenin progesterone therapyasprimaryandalso response rateforpatientstreatedwithhigh-dose treatment. These studieshighlighta50to70%overall a temporaryresponse,and24%neverrespondedto demonstrated alastingcompleteresponse,25%showed Studies investigatingtheefficacy ofprogestintherapy Progestin-releasingIUDsusedinpatientswith 10 Inareviewofarticlespublishedbetween 11 Inaprospective,multicentertrial, 12 10 Ofthese133patients,51% 11 reviewed27articles 14 15 usedthe reporteda 8,9 8- by thedownregulationofprogesteronereceptors. lower responseseenwithhighdosesmaybeexplained that high-doseregimensyieldedworseresponse. The months forlow-doseversushigh-dosegroup,indicating 2.5 monthswithoverallsurvivalof11.1 versus7.0 response toprogestin. important prognosticfactorsthatpredictafavorable expression ofestrogenand/orprogesteronereceptorsas low-grade histology, longdisease-freeinterval,and tumors dorespond.Nevertheless,moststudiessupport respond totherapyandwhysomeER/PR-negative not clearwhysomanyreceptor-positive tumorsdonot respectively. MPA, withcompleteresponserateofonly17%and9%, low-dose (200mg/day)orhighdose(1000oral recurrent endometrialcancerwererandomizedtoeither Oncology Groupstudy, women withadvancedor Cancer Progestin Therapy inRecurrent Endometrial rates rangedfrom15to20%. multicenter cooperativestudies,theobjectiveresponse with morestringentresponsecriteriaandlarger (MPA, hydroxyprogesteronecaproate); rates ashigh56%withvarioustreatmentregimens therapeutic alternative.Earlystudiesreportedresponse advanced agewherehormonaltherapymaybea disease orpresentwithmultiplecomorbiditiesatan procedures, chemotherapy, orboth, withprogressive Many ofthesepatientshavealreadyundergone surgical patients withadvancedorrecurrentendometrialcancer. endometrium. Oneexample isthesignificantdecrease normal endometriumisvery different fromthediseased different. Furthermore, thetissuecompositionof mechanisms ofprogesterone actionareexpectedtobe cells arenotthesameas normal cells,andtherefore from thatofneoplasticormalignanttissues.Malignant response inthenormalendometriumisverydifferent recurring diseaseishighlysuggestivethatprogesterone The factthatprogestintherapyisoftenassociatedwith endometrial canceranddoesnoteradicatethedisease. is alsoamodeofpalliativetherapyforrecurrent well-differentiated endometrioidendometrialcancer. It eradicate somebutnotallendometrialhyperplasiaand cancer. Progestinsareusedin thecliniceffectively to is underlinedbyitsefficacy inpreventingendometrial progesterone incontrollingestrogen-drivenproliferation with unopposedestrogenaction. The significanceof Progesterone agentshavebeenextensivelyusedin Endometrial adenocarcinomaishighlyassociated 21 Progression-freesurvivalwas3.2versus 20,21 20,21 InamajorGynecologic 1,18,19 however, 21 It is .UshijimaK, Yahata H, Yoshikawa H.et al. 8. WheelerDT, BristowRE,KurmanRJ.Histologic 7. Randall TC, Kurman RJ.Progestintreatmentof 6. Varma R,SonejaH,BhatiaK.etal. The effectiveness 5. GalD,EdmanCD, Vellios F, ForneyJP. Long-term 4. Affinito P, DiCarloC,MauroP, Napolitano V, 3. SaegusaM,OkayasuI.Progesteronetherapyfor 2. ReifensteinJrEC. The treatmentofadvanced 1. prevent ortotreatendometrialcarcinoma. an areaworthinvestigatingtofurtherunderstandhow in modulatingglandulartransformationandwouldbe known oftherolestromainresponsetoprogesterone epithelium butalsobythestroma. There isverylittle dictated notonlybythehyperplasticormalignant compromised. Thus progesteroneresponsivenessmaybe sufficient stroma,progesteroneresponsewouldbe influences theepitheliuminaparacrinemanner. Without highly responsivetoprogesteroneanddynamically compared withcyclingendometrium. The stromais in theamountofstromaobservedendometrialcancer References Multicenter phaseIIstudy offertility-sparing J SurgPathol 2007;31(7):988-998 differentiated carcinomatreatedwithprogestins. Am alterations inendometrialhyperplasiaandwell- 40. ObstetGynecol1997;90(3):434-440 carcinoma oftheendometriuminwomenunderage atypical hyperplasiaandwell-differentiated ObstetGynecolReprodBiol 2008;139(2):169-175 hyperplasia—a long-termfollow-upstudy. EurJ (LNG-IUS) inthetreatmentofendometrial of alevonorgestrel-releasing intrauterinesystem 1983;146(3):316-322 endometrial hyperplasia. Am JObstetGynecol effect ofmegestrolacetateinthetreatment 3):191-198 micronized progesterone.Maturitas1994;20(2- treatment withavaginalcreamcontainingnatural Nappi C.Endometrialhyperplasia:efficacy ofanew does notalterapoptosis.Cancer1998;83(1):111-121 endometrial carcinomareducescellproliferationbut 1974;2(2-3):377-414 hydroxyprogesteronecaproate. GynecolOncol endometrial cancerwith 8 Decruze SB,GreenJA.Hormonetherapyin 18. PiverMS,BarlowJJ,LurainJR,Blumenson LE. 17. KelleyRM,Baker WH. Progestationalagentsinthe 16. KresowikJ,Ryan GL, Van Voorhis BJ.Progression 15. JonesK,Georgiou M,HyattD,Spencer T, Thomas 14. DharKK,NeedhiRajan T, KoslowskiM, Woolas RP. 13. MontzFJ,BristowRE,Bovicelli A, Tomacruz R, 12. Kim YB, Holschneider CH,GhoshK,Nieberg RK, 11. ChivaL,LapuenteF, González-CortijoL.etal. 10. RamirezPT, FrumovitzM,BodurkaDC,SunCC, 9. advanced andrecurrent endometrial cancer:a 1980;45(2):268-272 with metastaticendometrial adenocarcinoma.Cancer hydroxyprogesteronecaproate (Delalutin)inwomen Medroxyprogesterone acetate(Depo-Provera)vs. J Med1961;264:216-222 treatment ofcarcinomatheendometrium.NEngl 2):547-549 intrauterine system.ObstetGynecol2008;111(2 Pt treatment withthelevonorgestrel-releasing adenocarcinoma despiteintrauterineprogesterone of atypicalendometrialhyperplasiato 2002;87(2):216-218 insertion ofaMirenaIUCD.GynecolOncol H. Endometrialadenocarcinomafollowingthe 2005;97(3):924-927 cases andreviewoftheliterature.GynecolOncol treatment ofearlyendometrialcancer?Reportfour Is levonorgestrel intrauterinesystemeffective for 2002;186(4):651-657 early endometrialcancer. Am JObstetGynecol Kurman RJ.Intrauterineprogesteronetreatmentof Cancer 1997;79(2):320-327 Report ofsevencasesandreviewtheliterature. endometrial carcinomainpremenopausalwomen. Montz FJ.Progestinaloneasprimarytreatmentof S104 cancer. GynecolOncol2008;111(2, Suppl):S101- Sparing fertilityinyoungpatientswithendometrial review. GynecolOncol2004;95(1):133-138 of grade1endometrialadenocarcinoma:aliterature Levenback C.Hormonaltherapyforthemanagement young women.JClinOncol2007;25(19):2798-2803 endometrial carcinomaandatypicalhyperplasiain treatment withmedroxyprogesteroneacetatefor

69 FOGSI FOCUS 70 FOGSI FOCUS 1 QuinnMA,CauchiM,FortuneD.Endometrial 21. MarkmanM.Hormonaltherapyofendometrial 20. ThigpenJT, BradyMF, Alvarez RD.etal.Oral 19. 1985;21(3):314-319 medroxyprogesterone acetate.GynecolOncol carcinoma: steroidreceptorsandresponseto cancer. EurJCancer2005;41(5):673-675 J ClinOncol1999;17(6):1736-1744 response studybytheGynecologicOncologyGroup. advanced orrecurrentendometrialcarcinoma:adose- medroxyprogesterone acetateinthetreatmentof 2007;17(5):964-978 . IntJGynecolCancer form ofcontinuouscombinedregimen tolerated. Progesteronecanbegivencyclicallyorinthe irregular bleedingand,inaddition,shouldbewell the beneficialeffects ofestrogennor produce cyclicor endometrial hyperplasiaandcancer. estrogen forallwomenwithauterustoprevent symptoms. Progestogenshouldbeaddedtosystemic hormone willalleviatemajorityofmenopausal deprivation ofestrogen,theadministrationthis of relevance.Sincemenopausalsymptomsaredueto to multipleseveresymptoms.Inthesewomen,HRT is conditions whichmayrangefromfewmildcomplaints age. Manyofthesewomenneedtreatmentforvariety would spendonethirdoftheirlifeinpostmenopausal MENOPAUSAL THERAPY PROGESTERONE IN combined regimenwhichwill allowableedfreeHRT – menstrual period should switchtoa continuous of HRT, orisstartingHRT oneyearafterthelast of oneyear a minimum withdrawal bleedandhastaken withdrawal bleed.Inwomen whowishtoavoidamonthly 14 dayspermonth).Thisregimewillallowmonthly be started,i.e.continuousestrogenwithprogestogen(12– to startingHRT, asequentialcombinedregimen should menstrual periodhasoccurredlessthanoneyearprior Email: [email protected] The idealprogestogeninHRT should neithernegate With increasinglifeexpectancy, majorityofwomen Patna MedicalCollege, Secretary, PatnaObstetric& Gynaecological Society Dr. Abha RaniSinha Dept. ofObst&Gynae D.G.O., M.S.,FICOG Associate Professor 1,2 3 . Ifthelast ii Endometriodtumoursoftheovary (iii) Supracervicalhysterectomy (ii) (iv) i Women withpasthistoryofendometriosis– (i) women. estrogen maybeindicatedeveninhystrectomized these regimenswilleventuallybecompletelybleedfree. bleeding tobeginwith,but90%ofthosethatpersistwith with ultrasoundscanand/orendometrialbiopsy. problem beyondsixmonthsnecessitatesinvestigation duration increasedto21days. A persistentbleeding regimen, thedoseofprogestogencanbedoubledor another year. Ifbleedingisheavyorerraticonasequential be switchedbacktoasequentialregimenforatleast settle afterthreetosixmonths,thenthewomanshould switching tocontinuouscombinedHRT anddoesnot hyperplasia. Ifbreakthroughbleedingoccursafter this willalsominimisetheriskofendometrial In thefollowingsituationsprogesteronealongwith With boththeregimens,theremaybesomeerratic with unopposedestrogen patients withpelvicendometriosisbeingtreated because adenocarcinomahasbeenreportedin Adenocarcinoma oftheendometrium Email: Patna MedicalCollege, Dept. ofObst&Gynae Senior Resident D.G.O., M.S., Dr. SushmaSingh [email protected] 4 . 12 5 .

71 FOGSI FOCUS 72 FOGSI FOCUS depression effects includebreasttenderness,bloatingand estrogen withprogestinis determinedbythetypeof calcium balance increase inboneformation associatedwithapositive estrogen,Progestins canapparently exhibitasynergistic reduce boneresorption but theyhavebeenreportedtoactindependently to disturbances. Estrogen, thisisagoodchoiceforwomenwithsleep progesterone shouldbetakenatbedtimeandwith sedative effect. Treatment regimenswithmicronized pregnanlone areresponsibleforprogesteronesunique on moodcomparedwithMPA containingregimens but isnotaseffective asestrogen receptor specificity. generally havefewersideeffects duetoprogesterone and endometrialsampling,ifclinicallyindicated. there shouldbealowthresholdforultrasoundscanning bleeding problemsandhyperplasia.Sointhesewomen to seventendays.Thismaysometimesresultin be halvedanddurationofprogestogencanreduced nervous systemprogesteronereceptors. effects result fromadversestimulationofthecentral receptors. progestogens duetostimulationoftheandrogen hirsuitism areaproblemofthetestosteronederived receptors. Androgenic sideeffects suchasacneand system, triggeredbystimulationofthealdosterone by thesodiumretainingeffect oftherenin-aldosterone HRT isthatofprogestogenintolerance Progestational agentsareconsideredantioestogenic Two metabolitiesofprogesteroneallopregnanlone& Micronized progesteronemayexertsuperioreffects Quality oflife(QOL) Progestogen alonealsoreducesvasomotorsymptoms Vasomotor Symptoms Benefits ofProgesterone inHRT Micronized progesteroneanddydrogesterone To minimiseprogestogenicsideeffects, thedosecan Mood swingsandPremenstrualsyndromelikeside One ofthemainfactorsforreducedcompliancewith Side effects 7,8 . Symptomsoffluidretentionareproduced 12,13 .The synergistic resultofcombining 11 . When addedto 9 . 6 . Typicalside 10 . given regimen study, allprogestogensperformedsimilarly within a risk, particularlywithlong-cycle progestogen.Inthis sequential progestogentherapy withETincreasedthe endometrial neoplasiacompared tonouseofHT, and reported thatcontinuoususeofEPTreducedtherisk of progesterone. A long-term Finnishobservationalstudy acetate, 0.5mgdrospirenone,or100micronized medroxyprogesterone acetate,0.1mgnorethindrone Typically thelowesteffective dosesisused-1.5mg different regimesforprovidingendometrialsafety. risk [RR],1.13;95%CI,0.73-1.76) entry hadnosignificanteffect onriskofstroke(relative ET trials,HTinyoungerwomen(ages50-59y)atstudy analyses thatcombinedresultsfromthe WHI EPT and per10,000womenyearofET. Inrecent per 10,000womenyearofEPT and11 additional cohort wasanalyzed,therewereeightadditionalstrokes risk ofhemorrhagicstroke.Inthesetrials,whentheentire increased riskofischemicstrokeandnoeffect onthe and 2.7casesper10,000yearfortheplacebogroup years ofuse. Therewere 4.2casesper10,000forHT users significant increaseinovariancancerafterameanof5.6 cancer, EPT wasnotassociatedwithastatistically belonging to19–nortestosteronefamily progestin. This effect isobservedwithprogestins cancer withallEPTformulationslong-termuse short-term usebutcarriesanincreasedriskofbreast progesterone carriesalowriskofbreastcancerwith observational studysuggestthatEPTwithmicronized with continuoususeofprogestogen.Datafromalarge observational studiessuggestingthatriskmaybegreater continuous andsequentialuseofprogestogen,with have notclarifiedwhethertheriskdiffers between per 10,000womenusingEPT for5ormoreyears.Studies risk, inabsoluteterms,waseightadditionalbreastcancers beyond 3to5years.Inthe WHI overall,thisincreased Progestogens canbeusedindifferent dosesand Dose androute ofadministration The WHI EPT andET trialsdemonstratedan In the WHI, theonlyRCT todatestudyovarian Ovarian Cancer Diagnosis ofbreastcancerincreaseswithEPTuse Breast cancer Risks 21 . 18,19,20 14 . . 15,16 17 . . most patients endoemetrium andisassociatedwithamenorrhoeain commercial preparationtwiceweeklyprotectsthe changes intheendometrium. An application ofthe4% administration of90mgevery2daysproducessecretary .BeresfordSA,weissNS,Voigt LF,McknightB,Riskof 3. McGonigleKF,Karlan BY ,BarbutoPALeuchterRS, 2. FeldmanS,ShapterA,WelchWR,BerkowitzRS,Two 1. levels becauseofbypasseffect ontheuterus effectively protecttheendometriumwithlowsystemic which allowsthedeliveryofaverylowdosethatcan acetate 0.250mgorLNG0.010mg. 0.04mg/daily andinsequentialregimenorethidrone or LNGindailydoseof0.007,0.0150.030and norethidrone acetateinadailydoseof0.140or0.250mg estrogen andprogesteronecombinationincorporate demonstrated endometrialprotection. The and combinedprogestogen-estrogenmatrixpatcheshave progestogen givensequentially continuously andsuperiorprotectioncomparedwith provided bysystemicprogestogenadministered provide endometrialprotectionequivalentto progestin-containing intrauterinesystemwasfoundto ET inperimenopausalandpostmenopausalwomen,the women areamenorrheic. months andafteroneyearapproximately60-70%ofthe There isirregularbreakthroughbleedinginthefirstsix protection andescapessystemicprogestinsideeffects. cancer. The localsiteofactionprovidesendometrial menopausalwomen.Lancet 349;458,1997 combined withcyclicprogestogen therapyinpost endometrial cancerinrelation touseofoestrogen replacement therapy.Gynecoloncol 55:126,1994 cancer inwomenonoestrogenandprogestinhormone LagasseLD,JuddHL,Development ofendometrial biopsy,Gynecoloncol 55:56,1994 perimenopausal vaginalbleedingandnegativeinitial year followupof263patientswithpost/ References:- Progesterone canbeadministeredinavaginalgel Oral progestogens,combinedwithsystemicestrogen, A smallstudyreportedthatwhenusedwithsystemic It protectstheendometriumagainsthyperplasiaand Progesterone IUCD(MIRENA) 23 . 24,25,26 . 22 . The 14.SperoffL,RowanJ,Symons J,GenantH, WilbornW, for 13. GallagherJC,KableWT,GoldgarD,Effect ofprogestin SelbyPL,PeacockM,BarkworthSA,BrownWB, 12. JC,VignaYM,BarrSI,RexworthyC,11.Prior LentleBC, deLignieresB, Vincens M.Differential effects 10. Schiff I, Tulchinsky D, CramerD,Ryan KJ.Oral 9. PriorJC,AlojadoN,MckayDW,VignoYM,No adverse 8. 5.KirkhamC,HahnPM, VanwgilDA, CarmichaelTA, 7. PanayN,StuddJWW.Progestogen intolerance& 6. McMeekinDS,Burger RA,Manetta A, DiSaiaP, 5. ReimnitzC,BrandE,Nieberg RK,HackerNF, 4. 276;1397,1996 hormones asreplacement therapy,JAMA density,endometrium,and lipidsofcontinuous the chartstudygroup,Thecomparativeeffect onbone with estrogen Am JMed90;171,1991. therapy oncorticalandtrabecularbone:comparison hormones,ClinSci 69;265,1985 on boneresorptionandcalciumregulating Norethisterone treatmentinpostmeopausalwomen Taylor GA,Earlyeffects ofEthinylestradioland menstrual cycledisturbances,AmJMed96;521,1994 density;a controlledtrialinactivewomanwith Cyclicmedroxyprogestone treatmentincreasesbone relationship. Maturitas1982;4:67. in post-menopausalwomen:Individualdose/effect of exogenousoestradiolandprogesteroneonmood 1445. postmenopausal symptoms.JAMA1980;244:1443- medroxyprogesterone inthetreatmentof 83:24,1994 controlled,cross-over trial,ObstetGynaecol in postmenopausalwomen;double-blind,placebo– effects ofMedroxyprogesterone.T/twithoutestrogen ObstetGynaecol 78;93,1991 ReidRL,Arandomised, double-blind,PlaceboHRT, HumReprodUpd 1997;3:159-171 compliance withHRT inmenopausalwomen. GynecolOncol 59:81,1995. anditsrelationshiptoendometriosis, Berman M,Endometrioidadenocarcinomaofthe 71:444, 1988. unopposed estrogenreplacement,ObstetGynecol Malignancy arisinginendometriosisassociatedwith

73 FOGSI FOCUS 74 FOGSI FOCUS 21. JaakkolaS,Lyytinen H,PukkalaE, Ylikorkala O. 20. RossouwJE,PrenticeRL,Mansonetal. 19. HendrixSL, Wassertheil-Smoller S,JohnsonKC,et 18. Wassertheil-Smoller S,HendrixSL, Limacher M,et 17. Anderson GL,JuddHL,Kaunitz AM, etal,forthe 16. Fournier A, MesrineS,Boutron-RuaultMC,Clavel- 15. ChlebowskiRT, HendrixSL,LangerRD,etal,for 2009;114:1197-1204. estradiol-progestin therapy. ObstetGynecol Endometrial cancerinpostmenopausalwomenusing menopause. JAMA2007;297:1465-1477 cardiovascular diseasebyageandyearssince Postmenopausal hormonetherapyandriskof Circulation 2006;113:2425-2434. Women’s HealthInitiative:arandomized trial. Effects ofestrogenplusprogestinonstrokeinthe al, forthe Women’s HealthInitiativeInvestigators. 2003;289:2673-2684 Women’s HealthInitiative:arandomizedtrial.JAMA progestin onstrokeinpostmenopausalwomen. The al, forthe WHI Investigators.Effect ofestrogenplus 2003;290:1739-1748. Health InitiativeRandomized Trial. JAMA associated diagnosticprocedures. The Women’s estrogen plusprogestinongynaecologiccancersand Women’s HealthInitiativeInvestigators.Effects of risks? JClinOncol2009;27:5138-5143. menopause onsettotreatmentinitiationinfluence hormone therapyandbreastcancer:doesdelayfrom Chapelon F. Estrogen-progestogenmenopausal 3253. Initiative Randomized Trial. JAMA 2003;289:3243- healthy postmenopausalwomen:the Women’s Health progestin onbreastcancerandmammographyin the WHI Investigators.Influenceofestrogenplus 26. SomboonpornW, PannaS, Temtanakitpaisan T, G,25. AnderssonJ,Ryboreleasing Levonorgestrel 24. Raudaskoski TH, LahtilEI,Kauppila AJ, A paja– 23. RossD,Cooper AJ, Pryse-DaviesJ,Bergeron C, 22. MilesRA,PressMF,Paulson RJ,DahmoushL, analysis. Menopause2011;18: 1060-1066. postmenopausal women:systematicreviewandmeta- estrogen therapyinperimenopausaland levonorgestrel-releasing intrauterine systemplus Kaewrudee S,SoontrapaS.Effects ofthe ObstetGynecol 97:690,1990, intrauterine deviceintreatmentofmenorrhagia,BrJ response,Am JobstetGynecol172;114,1995 climacteric complaints:clinicalandendometrial with aLNGreleasingintrauterinedevicefor SarkkinenMA,LaatikainenTJ,Transdermal estrogen 177:937, 1997. postmenopausal women, Am JObstetGynecol of avaginalprogesteronegelinestrogen-treated blind, dose-rangingstudyoftheendometrialeffects Collins WP, Whitehead MI,Randomized,double- comparative study,Fertilsteril 62:485,1994 administration byintramuscularandvaginalroutes:a endometrial tissuelevelsofprogesteroneafter LoboRA, SaucerMV, Pharmacokineticsand intrauterine systemaswell. be givenbyintramuscular, vaginal,rectal,topicalandas progestogens orprogestins. routes. These arecalledprogestationalagents, progesterone likeactivitiesandcanbegivenbydifferent during pregnancy. second halfofthemenstrualcycleandfromplacenta primarily fromthecorpusluteumofovaryduring carbon steroid)derivedfromcholesterol.Itissecreted with ,areusedfor: DRUG DELIVERY SYSTEMS PROGESTERONE: DIFFERENT Prakash MemorialClinic,Islampur A. Oral Route Apart fromtraditionaloralrouteprogesteronescan ROUTES OF ADMINISTRATION A numberofcompoundsaresynthesizedhaving Progesterone isanaturalsteroidalhormone(21 INTRODUCTION .Abnormal uterinebleeding(AUB) 3. Hirsutism PCOS, Acne, 2. Contraception 1. These eitheraloneorasCOCsi.e.incombination Dr. Mrs.SaieG.Mandrupkar Synthetic pr Islampur (ISO9001:2008) Consultant, Ob-Gyn Mandrupkar Clinic, ogestins MBBS DGO : applications. formulations forvariety ofclinicalandresearch effective alternativetosyntheticandnaturalprogesterone the oralabsorptionofprogesterone. capsules. The processofmicronizationhasbenefitted particulate powderandaredispensedinsoftgelatin and aresuspendedinoilascreamywhitecrystalline plant andisconvertedintoprogesterone. that istakenfromthe contains asteroidcalleddiosgenin techniques (ART). Otherobstetricusesofprogesterone Micronized naturalprogesteroneisnowasafeand Nowadays, allnaturalprogesteronesaresynthesized Plant sourcefortheseis It iswidelyusedininfertility andassistedreproductive B. PremenstrualdysphoricDisorder(PMDD) 8. Premenstrualsyndrome(PMS) 7. Treatment ofEndometriosis 6. Postponement ofmenses. 5. Dysmenorrhea 4. Natural pr 1 ogester Bichkar Hospital,Karad Consultant, Ob-Gyn MD Dr. Mrs.SonaliBichkar ones: Dioscorea Mexicana. 13 It

75 FOGSI FOCUS 76 FOGSI FOCUS with large boreneedleevery3months(90days). approved themarketingofDMPA ascontraceptiveagent. pregnancy maintenance. includes contraceptionwhilenaturaloneisusedin bioavailability. labor. The disadvantageisnauseaanddecreased include treatmentofthreatenedabortionandpreterm producing sorenessandinflammation atinjectionsites. Disadvantage isoilydaily injectionwiththickneedles injections ofnaturalmicronizedprogesteroneisused. bioavailability andpatientfactoristhereintramuscular Though vaginalrouteisfavored,insomecaseswhere pregnancy supportandpreventionofpretermlabor. progestin (104mginsteadof150mg)every3months. DMPA greater withlongerdurationofusagedrug. Advantages: It isgivenasadeepI.M.injectioninglutealregion In 1992,thefoodanddrugadministration(FDA) The gynecologicaluseofI.M.progesteronemainly Intramuscular injections Obstetric usesofprogesteroneincludeearly A newmicronizedpreparationas Disadvantages: isapprovedbyUSFDA.Ithasalowerdoseof Loss ofbonemineraldensity. The bonelossis 70% incidenceofirregularbleeding It doesnotinterferewithmilkproduction. No estrogen-relatedsideeffects It isindependentofcoitalactivity. subcutaneous of is50µg. 70 mgoflevonorgestrel respectively. The dailyrelease silastic rods,6or2innumber, eachcontaining36mgor levonorgestrel implantsconsistofthedrugenclosedin or desogestrelmetabolite,3-keto-desogestrel. The contraceptives. The implants consist oflevonorgestrel purpose. They aremoreeffective thanoralandbarrier on bonemarrowdensity(whichisasideeffect of DMPA). acting, highlyeffective, reversible,and havenoeffect minimal incisionunderlocalanesthesia. is 5andwithdesogestrel3years. years. 70 µg/day. containing 68mgofthedrug. The initialreleaseis60- The 3-keto-desogestrelimplantisa These aremainlyusedsubdermallyforcontraceptive Implants Vaginal Route Progesterone implantsascontraceptivesarelong Formulations areimplantedsubdermallywith The contraceptiveefficacy oflevonorgestrel implants This reducesto25-30µg/daybytheuseof3 obstetric indications. favorable routefor vaginal routeisnowmost progesterone bythe natural micronized cream orring.Useof suppository, vaginalgel, form ofcapsule,, used byvaginalrouteinthe Progesterone canbe single rod vaginal routeinpreventionofpretermlabor. as bleeding. vaginal administrationnotpossibleduetocausessuch secretions. body anddrugisreleased. Upon insertion,thesuppositorymeltsduetowarmthof -based Ø spray andpatches. Acontraceptive Ø Ø Progesteroneisalsoavailableas Ø Topical Route Natural micronizedprogesteroneisrecommendedby Rectal administrationcanbedonealternativelyif Gel Tablets Suppository Progesterone isavailableintheformofgel,cream, then 4 µg norelgestrominisavailableforcontraception. application. daily ontheskinrotating the siteofapplicationin . Itisadministeredas1-5sprays withdrawal bleeding. A newpatchisappliedeachweekfor3weeksand Creams helpstocoatthevaginalwalls. areeffervescent andtheydissolveinvaginal th tendtogetpoorlyabsorbedthroughtheskin. week ispatchfreewhenpatientgets containsprogesteroneinawaxbase. patch are effective withonceaday releasing20µgEEand150 spray 2,3 for countries, arefoundtobelesseffective. available forcontraceptiveuse. EE) and120µgofprogestin(etonorgestrel) perdayis progestin, releasing15µgofestrogen( made upofethinylvinylacetatecontainingestrogenand andendometriosis. help intreatmentoffibroid andDUBpossiblyin effects. Someformulationshavebeenshown tobeof estrogen anddecreasedIUCD-related menstrualside the advantageofbeingdevoid ofthesideeffects of uterine progesteronecontraceptivedevices,thesehave progesterone isusedforcontraception. Also calledintra- required ismuchless. Only progestincontainingrings,availableinsome Avoidance offirstpasshepaticmetabolism. A combinedhormonalcontraceptivevaginalring Highbioavailability. · Rapidabsorption · Patientcompliance · · Advantages: Intra- uterinecontraceptivedeviceimpregnatedwith Impregnated lntra-uterineContraceptiveDevice Due toavoidanceoffirstpasseffect of liverdosage This iseffective, easytouse,welltolerated,andsafe. contains 6mgofnaturalprogesterone. the secondhalfofcycle.Each0.19mlspray

77 FOGSI FOCUS 78 FOGSI FOCUS contraceptive) become popularforclinicaluse. Organization (WHO)in1978.However, thisdidnot contraception hasbeenstudiedbytheworldHealth bleeding. of thepromisingtreatmentsdysfunctionaluterine initially and10µg/daylateronafter5years. which isreleasedinuterinecavityatarateof20µg/day opaque. impregnated withbariumsulphateformakingitradio- Levonorgestrel. hormonal intrauterinesystemthatcontains LNG IUS(Intrauterineprogesterone Use ofprogesteroneinnasalsprayformfor Nasal Spray Reductioninendometrialca/hyperplasia. § Symptomaticimprovementinendometriosis § Reductioninsizeoffibroids § Reduced menstrualpain. § Other advantages: It isnotonlylicensedforcontraceptionbutalsoone Cylindrical reservoircontains52mgLevonorgestrel It has32mmlong,flexibleplastic T shapedframe Levonorgestrel intrauterine system(LNG-IUS)isthe .Wang LJ,HuangFJ,KungFT, etal.Comparisonof 3. ACOG CommitteeOpinionnumber419October SocietyforMaternalFetalMedicinePublication 2. GoletianiNV, KeithDR,GorskySJ.Progesterone: 1. Taiwan JObstetGynecol2009;48:375-9. luteal supportinblastocyststageembryotransfers. crinone 8%gelandutrogestancapsules,usedfor the efficacy oftwovaginalprogesteroneformulations, birth.OstestGynecol 2008;112: 963-5 2008.Use ofprogesteronetoreducepreterm Committee. studies.ExpClinPshychopharmacol 2007;15:427-44. review Ofsafetyforclical References: nomegesterol acetatearecalledasnewprogestins desogestrel, gestodene,dienogest,drospirenone, generations. Third andfourthgenerationprogestins improved selectivityprofileshasbeenagreatchallenge. development ofnewgenerationsprogestinswith activity butsomewhatantiandrogenic. recirculation hasnoglucocorticoid ormineralocorticoid antigonadotropic. Itundergoes enterohepatic hydroxy 19-norprogesterone derivativeishighly generation progestinslike derivatives are different classesofsynthetic progestinsandits maintains pregnancy. Besidesnaturalprogesterone, there which regulatespostovulatorymenstrualcycleand ITS METABOLITES PROGRESTERONE AND NEW RESEARCHON Norgestimate metabolite 3-keto-desogestrelalsoknownasetonogestrel. areverysimilartolevonorgestrel. All 3 oral contraceptivepills(OCPs)areclassified Globulin (SHBG)anddecreasedfreetestosteronelevels. because ofincreasedbindingtoSerumHormoneBinding norgestimate J.N.Medical College, AMU, Aligarh Desogestrel Progesterone isanaturallyoccurringsteroidhormone Nomegesterol Acetate (NOMAc) Nomegesterol Acetate [email protected] 1 . According totheprogesteronecomponent M.S. (OBST. &GYNAE) Asst. Prof.Obstetrics& 4 anewprodruganditsactivemetabolite havenegligibleandrogenicactivity DR. NAZIA ISHRAT 3 isprodrugtransformstoactive Gynecology E MAIL- desogestrel , 4 gestodene , a new 2 intofour 1,2

17 a- . The and rd Uterine Bleeding(AUB). with ethinylvalerateitisalsobeingusedin Abnormal bond. Introducedasanoralcontraceptiveincombination group insteadofethylatC-17andanextradouble delivery system. ,subcutaneousimplantandtransdermal effect andevolvedforcontraceptionintheformof receptor isnegligible.Itshowshighovulationinhibition affinity toprogesteronereceptorbutbindingandrogen quick metabolizationinliver. Itshowshighbinding blood pressureandimprovementofacne. with goodcyclecontrol,decreaseinbodyweightand equal contraceptiveefficacy tosecondgenerationOCPs (OCPs) containing3mgdrospirenoneand30gEEshows and androgenicreceptors.Oralcontraceptivepills shows highaffinity forprogesterone,mineralocorticoid Drospirenone Dienogest Nesterone 6 5 isa19-nortestosteronewithcynomethyl

is onlyactiveparenterallybecauseof 7 isaspironolactonederivativewhich [email protected] E Mail:- J.N.Medical College, AMU, Aligarh Professor, Obstetrics&Gynecology MD, FICOG,FICMCH PROF. SEEMA HAKIM 14

79 FOGSI FOCUS 80 FOGSI FOCUS post menopausalwomen endometrial hyperplasiaandmenorrhagiaintheperi-and per dayisbeingdevelopedforthetreatment of Fibroplant contains 52mgLNGreleasing20µg/dayfor5years. levonorgestral releasingintrauterine system(LNG-IUS) level disease byinhibitingsicklingandincreasinghemoglobin endometrial cancer. Italsobenefitspatientofsicklecell with decreaseinanemia,PID,ectopicpregnancyand showed completeovulationinhibitionfor13weeksalong gestodene thantheOCPscontaininglevonorgestrel thromboembolism withOCPscontainingdesogestreland has shown2.6timesgreaterriskofvenous cardiovascular diseases favourable lipoproteinprofile&thusprotectsagainst do notimpaircarbohydratestolerence. They alsohavea administered subcutaneously of thromboembolism diabetics, hypertensivewomenandwithhistory preferably usedinlactatingwomen,womenoverage40, history ofthrombosis. carriers offactor V Leidenmutation,womenwithfamily prescribing newprogestinstosmokers,users, inference maybeduetosomeconfoundingfactorslike choice after3weekspostpartum. LNG-IUSisanequally mg levonorgestrel isalsoequallyeffective. combined estrogen-progesterone pills.Singledoseof1.5 in 2dosesof0.75mg12hoursapartisbetterthanthe cause weightgain,acneandhirsutism progestins. Becauseoflessandrogenicity, theydonot Contraceptive- PROGESTERONE period andagreaterovulationinhibition new desogestrelcontainingPOPsallowa12hourgrace or levonorgestrel aretakendailyatthesametimebut medroxyprogesterone acetate Progesterone containing IUCDs (b) (d) (c) EmergencyContraception- Recent OCPscontainslowdoseestrogenandnew CombinedEstrogen -Progesterone (a) RECENT ADVANCES INCLINICAL USESOF Progesterone OnlyPills(POPs) Depo-subQ Provera 104 2 . PostpartumContraception- Progesterone OnlyContraceptives , anewshorterdevicereleasing14µgLNG 3 . 8 . Buta WHO collaborativestudy 11 . 10 . SubcutaneousDMPA a

new lowdosedepot ( Levonorgestrel alone containingnorgestrel POPs canbeagood DMPA) isbeing 5 . Newprogestins like 4 . - They are - They Mirena 9 . This , hirsutism andacne with COCs(reversesequentialregimen)incaseofsevere Cyproterone acetateisaddedtofirst10daysofcycle show improvementinacneandhirsutism.50-100mg containing thirdgenerationprogesteroneordrospirenone women approachingmenopause Progesterone therapyisidealinpuberty, adolescentand Progesterone aremoreeffective inanovulatory AUB. loss duetonatriureticaction. antimineralocorticoid whichisassociatedwithweight is moreeffective thanoralroute Micronised naturalprogesteronewhengivenvaginally and canbegivenbyoral,vaginalintramuscularroute. progesterone isstandardprotocolforlutealphasesupport progesterone vaginallyupto34weeksofgestation TVS at24weekswereprescribed200mgmicronized European trialforpatientswithshortcervix(<2cm)on recommended forpatientsatriskofpretermlabour. In PROGESTERONE in thebonemassdensity forlongtermuseinfibroid,thereisnoreduction Progesterone combinationwhenaddedwithGnRH hemoglobin andserumironlevelrises.Estrogen- uterine fibroids. There isdecreaseinuterinevolume but blood lossanddysmenorrheaupto50%inpatients of section effective alternative.Itcanbeusedevenduringcesarean changes andmood are observedtoimprovewaterretention,behavioral dysmorphic disorders- dysmenorrhic symptoms. and LNG-IUShavedemonstratedreductionin decreasing frequencyofmensus. Vaginal ring,Implant days) areeffective intreatingdysmenorrheaby choice fortreatmentof endometriosisbecause decidualization ofendometrium. Progestinsarefirst hyperprogestogenic hypoestrogenic statecausing 3 AcneandHirsutism- (3) 6 AbnormalUterineBleeding(AUB)- (6) Lutealphasesupport- (2) 1 PreventionofPretermlabour- (1) NON CONTRACEPTIVEUSESOF 7 Uterinefibroids- (7) 5 Pre-menstrualtensionorPremenstrual (5) Primarydysmenorrhea (4) 8 Endometriosis (8) 12 . 2 . DrospirenonecontainingOCPs 16 - Progesteroneinduces a

. LNG-IUS reducesmenstrual Oralcontraceptivepills 7 - Extendedregimens(84 14 . Drospirenoneisan 15 . . During ART, Progesterone is 13 . progestins usedinHRT block celldeathinbreastwhichisaffected by specific cellmembraneproteinPGRMC-1isfoundto can alterthedrugstoprooranti-cancermoieties. A to establishwhetherprogesteronemetabolizingenzymes progesterone metabolisminbreasttissueandcelllines breast carcinoma.Researchesaregoingontodetermine So theprogesteronemoleculeseemstobeimplicatedin response toestrogentherapy, butsomeareunresponsive. hormones, asonethirdofthepatientsshowsome changes inbreastcancercellsareduetoovarian ongoing contraception the GnRHagonistswithfewersideeffects andproviding endometriosis byreducingpain,bettersuppressionthan LNG-IUS hasbeneficialeffects inthetreatmentof comparable effectiveness asdanazolorGnRHanalogue. endometriosis leuprolide acetateinrelievingpainassociatedwith daily for6monthsdemonstratedequalresultstodepot nicotinic cholinergic receptors. Progesteronehasan neurotransmitter receptors- GABA,glycine,serotonin3, neuronal signaling. They interactwithseveral like allopregnanoloneand pregnanoloneregulate 14 daysofthecycleorcontinuously. present. Progestincanbeusedcyclicallyforlast12to HRT forpostmenopausalwomenwhoseuterusis Progesterone incombinationwithestrogenisusedasan carcinoma aresuitableforprogesteronetherapy... and longtermdisability after thebraintraumahasshownreducedriskofdeath patients ofheadinjury, progesteronewasgivenshortly preventing celldeath.Ina3yearPhaseIIItrialonthe 19-nor progesteronesincreaseBcl-2expression specific proteinsbyoligodendrocytes.Progesteroneand increases neuronalsurvivalandsynthesisofmyelin ablation The resultsarecomparablewithsurgery orendometrial effective inendometrialhyperplasiaandmenorrhagia. the localactiononendometriumLNG-IUSisvery number ofestrogenandprogesteronereceptors.Dueto carcinoma Role ofprogestins inbreast cancer- RECENT RESEARCHESINPROGESTERONE Roleinepilepsy- (10) Role ofprogesterone inbrain injury 9 EndometrialHyperplasiaand (9) Hormone ReplacementTherapy(HRT)- 19 Well differentiated gradeIendometrial - The medicaltherapydependsuponthe 18 . 17 Progesterone anditsmetabolites . A trialwithdienogest2mggiven 21 22 . . – Progesterone Proliferative development. progesterone canbeascopeoffutureresearchand Neuroprotection andmyelinregenerationby role ofprogestinsinHRT incausingbreastcarcinoma. Epidemiologic studieshavecreatedcontroversiesamong women withfamilyhistoryofthromboembolism. the smokers,womenwithfacter V Leidenmutationand tolerated. Buttheyshouldbeprescribedcautiously to similar tonaturalprogesterone,lessandrogenicandwell for contraceptionandhormonereplacementtherapyare pharmacological actions. The newprogestinsdeveloped differences intheirstructure,metabolitesand contraception testosterone enanthateisbeingusedformale Leydig cells.Progesteroneincombinationwith sperm capacitationandbiosynthesisoftestosteronein Ca which cancausecoronaryarterydisease. prostanoid receptorscausingcoronaryhyperreactivity progesterone cancausedecreaseinvascularthromboxane during stress are neurosteroidswhichregulatecatecholaminesecretion evaluated fortreatmentofnicotineaddiction progesterone levelsarelow. Progesteroneisbeing substances thatenhanceserotoninactivitywhen function inthebrain.Sopeopleresorttonicotinelike breakdown ofserotoninandenhancesreceptor cognitive function. women elasticity andfirmnessinperipostmenopausal nor derivatives. Topical 2%progesteroneincreasesskin reductase activityisinhibitedbyprogesteroneand19- dysfunction inmales. seizure thresholdandreducesepileptiformactivity THP andactionatGABAreceptorcomplex.Itincreases antiseizure effect duetoitsmetabolite3-alpha,5-alpha- +2 Progestins arenotsimilarintheiractionduetolarge SUMMARY Roleinmalecontraception Role incoronary hyperreactivity Role instress- Role innicotineaddiction Roleinskinelasticityandbonedensity increase seemstoberelatedwithspermmotility, 27 . 24 . Itmodulatesrewardsystemandimproves 26 . Progesteronecanbeusedinerectile Progesterone andallopregnanolone Progesterone stimulated Progesterone inhibits Lowlevelsof skin5-alpha 25 . 23 .

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