57 1

s giatti and others Progestins in the brain 57: 2 R109–R126 Review

The other side of progestins: effects in the brain

Correspondence Silvia Giatti, Roberto Cosimo Melcangi and Marzia Pesaresi should be addressed Department of Pharmacological and Biomolecular Sciences, Center of Excellence on Neurodegenerative to R C Melcangi Diseases, Università degli Studi di Milano, Milan, Italy Email [email protected]

Abstract

Progestins are a broad class of progestational agents widely differing in their Key Words chemical structures and pharmacological properties. Despite emerging data ff progesterone suggest that progestins, besides their action as endometrial protection, can also have ff testosterone multiple nonreproductive functions, much remains to be discovered regarding the ff combined oral actions exerted by these molecules in the nervous system. Here, we report the role contraceptive exerted by different progestins, currently used for contraception or in postmenopausal ff hormone replacement therapy hormone replacement therapies, in regulating cognitive functions as well as social ff neuroprotection behavior and mood. We provide evidence that the effects and mechanisms underlying their actions are still confusing due to the use of different estrogens and progestins as well as different doses, duration of exposure, route of administration, baseline hormonal status and age of treated women. We also discuss the emerging issue concerning the relevant increase of these substances in the environment, able to deeply affect aquatic wildlife as well as to exert a possible influence in humans, which may be exposed to these compounds via contaminated drinking water and seafood. Journal of Molecular Endocrinology Finally, we report literature data showing the neurobiological action of progestins and in particular their importance during neurodegenerative events. This is extremely interesting, since some of the progestins currently used in clinical practice exert neuroprotective and anti-inflammatory effects in the nervous system, opening new promising opportunities for the use of these molecules as therapeutic agents for Journal of Molecular Endocrinology trauma and neurodegenerative disorders. (2016) 57, R109–R126

Introduction

An extensively demonstrated progesterone (PROG), (Giachino et al. 2003, 2004, Wang et al. 2008), produced in peripheral glands as well as directly in the astroglial, and synaptic plasticity (Luquin et al. 1993, nervous system (Melcangi et al. 2008, Porcu et al. 2016), McEwen & Woolley 1993, García-Segura et al. 1994, exerts important effects in the neuroendocrine control Murphy & Segal 2000, Reyna-Neyra et al. 2002, of reproduction and sexual behavior (Banks & Freeman Guerra-Araiza et al. 2007, Foy et al. 2008). Moreover, 1980, Barraclough et al. 1986, Skinner et al. 1998, this steroid regulates the development of some Micevych & Sinchak 2008, Schumacher et al. 2014), in neuronal types (i.e., Purkinje cells of the cerebellum) the modulation of stress responsiveness and anxiety- (Tsutsui et al. 2011), oligodendrocytes/Schwann like behavior (Barbaccia et al. 2001, Schumacher et al. cells (Jung-Testas et al. 1996, Ghoumari et al. 2005), 2014) as well as in the regulation of adult neurogenesis as well as the myelination process (Chan et al. 2000,

http://jme.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-16-0061 Printed in Great Britain Downloaded from Bioscientifica.com at 10/01/2021 06:44:53AM via free access

10.1530/JME-16-0061 Journal of Molecular Endocrinology identified subtypesmPGRδ (mPGR) three subtypesofreceptors:PROGmembranereceptors protein-coupled membrane receptors and include ( receptors (PAQR) andthesingle-transmembranePGRs seven-transmembrane progesteroneadiponectinQ different membrane-boundPROGreceptortypes:the nongenomic activityismainlymediatedbytwo transcription (Brinton receptors producesmultipleeffectsbyregulatinggene transcription factors.BindingofPROGtothese and PGR-B,whicharedefinedasligand-activated ( receptors (PGR)andmembrane-boundPROG receptors thatincludetheclassicnuclearprogesterone et al. 2014). the classical PGR can also mediate the effects of PROG affinity for PROG. It is also worth mentioning that PGMRC2, whichdisplaysmoderatelyhighbinding 25-Dx inratandHpr6human)thecloselyrelated membrane component one (PGMRC1, also termed as single-transmembrane PGRsareprogesteronereceptor Thomas 2008, reduce excitationintheCNS(Brinton these receptors block adenylate cyclase activity to 2013, PGRs Melcangi Thomas 2008, Fig. 1). Two major isoformsofPGRare known: PGR-A DOI: 10.1530/JME-16-0061 http://jme.endocrinology-journals.org Review Review Review These effects are mediated by an array of PROG α Hossain , β α , or , t al.2005, et β , and γ (7TMPRα 2015 ). Whenboundtoitsligand, et al. t al.2009, Do Regoet Singh γ , also referred to as transmembrane Roglio t al.2013).TheformerareG et , β t al.2008). PROG-induced et , γ ) andthetwomorerecently and mPGRε t al.2008, et s

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In thisstudy, datasofarobtainedwillbereviewed. functions. exerted by syntheticprogestinson the nervous the contrary, littleattentionwasaddressedontheactions 2015, system(Melcangi metabolites inthenervous have recently discussed the effects of PROG and its on theGABA-Areceptor(Wang 1991), butitantagonizestheeffectofallopregnanolone GABA-A receptor(Bäckström contrast, isopregnanolonedoesnotbinddirectlytothe receptor (PXR)(Cooke to bemediatedbyPAQR andbythepregnanexenobiotic Furthermore, several effects of allopregnanolone appear (Lambert the gamma-aminobutyricacidtypeA(GABA-A)receptor is apotentligandofnonclassicalsteroidreceptor, suchas receptor, thePGR(Melcangi its precursor, isabletointeractwiththeclassicalsteroid mechanism of action of PROG. Indeed, while DHP, like These enzymaticconversionshaveadeepimpactonthe oxidoreductase, respectively(Melcangi 3α-hydroxysteroid oxidoreductaseorβ converted intoallopregnanoloneorisopregnanoloneby (DHP) by the enzyme 5α-reductase. In turn, DHP is further Indeed, PROGisconvertedintodihydroprogesterone involvement ofmultiplereceptorsandsignalingpathways. system through the important effects in the nervous extranuclear mechanisms(Singh on signalingpathwaysthroughrapidnongenomic Progestins inthebrain Published byBioscientifica Ltd. Besides PROGitself,itsmetabolitesalsoexert Schumacher t al.2003, et receptor, promotingachloride(Cl allopregnanolone interactswithGABA-A intracellular signalingcascades.Furthermore, membrane components(PGMRC),promoting Q receptors(PAQR) andprogesterone receptor seven-transmembrane progesterone adiponectin of membranereceptorfamilies,suchasthe (see textfordetails)mayinteractwithmembers progesterone, allopregnanolone,andprogestins mineralocorticoid receptor. Moreover, estrogen receptor, glucocorticoidreceptor, and progesterone receptor, androgenreceptor, SR includesdifferent kindsofreceptors,suchas activating transcriptionoftargetgenes. the hormoneresponsiveelements(HRE),thus SR interactsintothenucleusasdimerwith cytoplasm. Afterbindingwithitsligand, coupled toheatshockproteins(HSP)inthe the intracellularsteroidreceptor(SR),whichis text, progesteroneandprogestinsinteractwith metabolites, andprogestins.Asreportedinthe mechanisms ofactionprogesterone,its Schematic representationofthedifferent Figure 1 et al. 2014, Belelli &Lambert2005)(Fig.1). t al.2013, et Downloaded fromBioscientifica.com at10/01/202106:44:53AM et al. 2008),allopregnanolone 2016, t al.2005, et et al. 2002).Manyreviews et al. 2013). Barros Frye Frye 57 57 : : 2 2 t al.2013).In et et al. 2015).On t al.2008). et Bitran – ) influx. 2014, et al. R110 R110 t al. et via freeaccess Journal of Molecular Endocrinology carbon (estrane),withamethyl groupatcarbon13and divided intothoserelatedto theparentsteroidwith18 Progestins belongingtothe ethinylated grouparefurther derivatives), conferringthem progestationalactivity. available nowfortherapeutic use(19-nortestosterone present inmostoftheprogestinsrelatedtotestosterone without destroyingtheoralactivity. Thischaracteristic is effect fromthatofanandrogentoaprogestogen to formnorethisteronechangedthemajorhormonal Subsequently, removalofthecarbon-19from ethisterone to thesynthesisoffirstoralprogestinethisterone. potency ofthesecompounds(Sobey2008).Thisled group intothetestosteronemoleculeincreasesoral substitution ofahydrogenonC17withanethinyl at carbon 17 and those nonethinylated (Fig. 2). The subdivided intothosecontaininganethinylgroup Progestins structurallyrelatedtotestosteroneare Progestins structurallyrelated totestosterone testosterone orPROG. two groupsbasedonthestructuralsimilaritieswith been synthesized. in theirchemicalstructuresandbiologicaleffect,have Hohlweg 1938),severalsyntheticprogestins,whichdiffer Inhoffen andWalter Hohlwegin1938(Inhoffen& 1996, Sitruk-Ware 2000). administration orinhibitionofovulation(Pasqualini greater bioavailability, half-life,andactivityafteroral been selectedonothercharacteristics,likeforinstance commonly usedinclinicalpractice,indeed,have of maintainingpregnancy. Syntheticprogestins support gestation,inthehumanonlyPROGiscapable endometriumand the capacitytoinducesecretory as compoundswithprogestationalactivity, meaning progestins (Stanczyk2003). progestational compounds. The latter are referred to as include boththenaturalhormonePROGandsynthetic refers tothebroadclassofprogestational agents. These be used. there isstillconfusionaboutwhichterminologyshould distinct toPROGbutdesignedtargetthePGR.However, terminology usedtodescribesyntheticsteroidsstructurally In recentyears,severalpapershavetriedtoclarifythe Chemical structure andmechanismofaction http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0061 Review Review These moleculesaregenerallyclassifiedinto From thefirstprogestin,synthesizedbyHansH. Although progestogensaregenerallyclassified The termprogestogensisafunctionaldefinitionand s

giatti © 2016SocietyforEndocrinology andothers Printed inGreatBritain activities (Kuhl2005,Rižner et al. 2011). negligible androgenic,estrogenic ormineralocorticoid of humanmineralocorticoid receptor(MR)andshows 2006). Inparticular, dydrogesteroneisinactive asagonists with theothersteroid hormone receptors (Colombo which issuitableforitsinteractionwithPGR,butnot is duetotherigidconformationofitsretrostructure, selective progestin,bindingalmostexclusivelyPGR.This bond betweencarbon6and7. the hydrogenatC9inβ presence ofthemethylgroupatcarbon10inα molecule isbent.Thisuniqueconformationduetothe four ringsinaplane)isalmostflat,retroprogesterone other progestogens,whosemolecularstructure(withthe one isastereoisomerofnaturalPROG.Comparedwith used progestinsintheUSA(Stanczyk&Bhavnani2014). acetate (MPA), isoneofthebest-knownandmostwidely 17α an acetylgroup.Amongtheacetylatedpregnane, separated intoclassesofcompoundswithandwithout Becerra et al.2004). receptors (Sitruk-Ware 2002, Schindler of thePGR,withlittleornoactivityforothersteroid promegestone (R5020)arethemostselectiveagonists particular, nomegestrolacetate,19-norprogesteroneand molecules tobindmore selectively tothePGR.In potency whencomparedwithpregnane, making these the 19-norpregnane derivatives higher progestational C19 ofthehydroxyprogesteroneskeletonconfersto 2003). ThedeletionoftheCH a methylgrouponcarbon10,respectively(Stanczyk (20 carbons)onthebasisofwhetherornottheycontain pregnanes 21carbons)and19-norpregnanederivatives subdivided into17-hydroxyprogesteronederivatives(or Progestins structurally related to PROG (Fig. 3) can be Progestins structurallyrelated toprogesterone has notbeenremoved. only exceptioninwhichthemethylgroupatcarbon10 compared with both estrane and 13-ethylgonanes, is the of the aldosterone antagonist spironolactone. DRSP, drospirenone (DRSP),whosestructureissimilartothat dienogest (DNG) and the spirolactone derivative also knownasgonanes)(Edgren&Stanczyk1999). those withanethylgroupatcarbon13(13-ethylgonanes, Progestins inthebrain Published byBioscientifica Ltd. -hydroxyprogesterone derivative medroxyprogesterone -hydroxyprogesterone derivative medroxyprogesterone Unlike otherprogestogens,dydrogesteroneisahighly Finally, theretroprogesteronederivativedydrogester­ Pregnanes and19-norpregnanesarefurther The nonethinylated group ofprogestinsincludes -position and an additional double -position andanadditionaldouble Downloaded fromBioscientifica.com at10/01/202106:44:53AM 3 radicalinposition 57 2003,García-et al. : 2 -position, -position, R111 et al. via freeaccess Journal of Molecular Endocrinology additional nonprogestagenic biologicaleffects. members ofthesteroid receptor family, exhibiting it isnotsurprisingthatthey canalsobindwithother derivates ofPROG,testosterone, andevenspirolactone, complex. Thus, considering that progestins can be and, in turn, the transcriptional activity of the dimer progestins influencestheirbindingaffinitywithreceptors properties andactions.Thechemicalstructure of for considerabledifferencesintheirpharmacological Small structuralchangesofprogestinsmayaccount Interaction ofprogestins withsteroid receptors DOI: 10.1530/JME-16-0061 http://jme.endocrinology-journals.org Review Review Review s

giatti © 2016SocietyforEndocrinology andothers Printed inGreatBritain Stanczyk et al.2013). in thereceptorinteraction (Conneely&Lydon 2000, according totheco-activators orco-repressorsinvolved be associatedwithanagonistic, antagonistic,ornoeffect of progestinswithoneormore receptors,inturn,may binding domainofthesteroidreceptor. The interaction chemical structureofboththeprogestinandligand- binding affinitiesforAR,ER,GR,andMRbasedonthe 2004). Progestinspresentcleardifferencesintheir glucocorticoid receptor (GR), and MR (Sitruk-Ware androgen receptor(AR),estrogen(ER), Progestins inthebrain Published byBioscientifica Ltd. Most progestins,indeed,alsointeractwiththe et al. (2010)andStuenkel(2015). asterisk (*)beforethename.DatafromLiu relevant progestinsareidentifiedwithan metabolites. Chemicalstructuresofclinically biochemical transformationtoactive prodrugs. Theselattermoleculesrequireinvivo drospirenone. Inthegraypanelsarereported by adottedlineisthespirolactonederivative line isthemoleculeoftestosterone,surrounded related totestosterone.Surroundedbyasolid Chemical structureofprogestinsstructurally Figure 2 Downloaded fromBioscientifica.com at10/01/202106:44:53AM 57 57 : : 2 2 R112 R112 via freeaccess Journal of Molecular Endocrinology 2013). Ontheotherhand,itis quitecommontofind receptors (Sitruk-Ware &Nath 2010, littleornoactivityforothersteroid the PGRwithvery nomogesterol acetate,arethe mostselectiveagonistsof promegestone, trimegestone (TMG),nestorone,and 1993, Bambergeret al.1999Raudrant&Rabe2003). whereas MPA transactivatesbothARandGR(McLeod acetate (CMA)arepotentanti-androgeniccompounds, cyproterone acetate(CPA), DNG,andchlormadinone

http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0061 Review Review The 19-norpregnanederivativeslike,forexample, Among 17-hydroxyprogesteronederivatives, s

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( Delyani 2000, antimineralocorticoid properties (Oelkers the well-knownMR antagonist spironolactone, has Becerra effects, also show a slightestrogenic activity (García- related totestosterone,besideshavingsomeandrogenic some reduced metabolites ofprogestinsstructurally norethisterone (NET),andtibolone(TIB).Moreover, related totestosteronelikelevonorgestrel(LNG), androgenic propertiesamongprogestinsstructurally Progestins inthebrain Muhn Published byBioscientifica Ltd. et al. 1995, t al. 2002). DRSP, since it is a derivative of et Oelkers 2004) and anti-androgenic effects and Stuenkelet al.(2015). (*) beforethename.DatafromLiuet al.(2010) relevant progestinsareidentifiedwithanasterisk dydrogesterone. Chemicalstructuresofclinically by adottedlineistheretroprogesterone line isthemoleculeofprogesterone,surrounded related toprogesterone.Surroundedbyasolid Chemical structureofprogestinsstructurally Figure 3 Krattenmacher 2000). Downloaded fromBioscientifica.com at10/01/202106:44:53AM 57 : 2 t al.1991, et R113 via freeaccess Journal of Molecular Endocrinology membrane PGRs(Falkenstein Schindler activity viatheAR(Fotherby1990, anti-androgenic activity, whereasnestoronehasno 2011) DNG,DRSP, andtrimegestonehaveasignificant (Germain overalldomainstructure exhibiting ahighlyconserved receptor superfamilyandhavestructuralsimilarity not surprising. All these proteins belong to the nuclear other steroid receptors (i.e., AR, ER, GR, MR) is indeed may beinfluencedbythe different expressionofsteroid tissues, thephysiologicaleffects ofaparticularprogestin greatlyindifferent levels ofdifferentreceptors canvary these receptors. synthetic compoundsintheCNScouldbemediatedby so wecannotexcludethatsomeoftheeffectsthese progestins for membrane PGRs are present in literature, (Thomas et al.2007). of theremainingprogestinstestedwerelessthan50% 50.9% comparedwiththatofPROG,whereastheRBAs displayed arelativebindingaffinity(RBA)of51.8and norprogesterone andpregna-4,9(11)-diene-3,20-dione (2007), amongthe30steroidalcompoundstested,only progestins tothisreceptor. AsshowedbyThomas littleisknownconcerningthepossiblebindingof very anti-androgenic activity(Lello2010, this lattergroup,nomegestrolacetateexhibitspartial Laws 1999),andthefourth-generationprogestins.In developed to decrease androgenic activity (LeBlanc & (desogestrel orgestodene),derivedfromLNGgroup, Among these, there are the third-generation progestins antimineralocorticoid effects(Africander action, alsoexertanti-estrogenic,antigonadotropic,and new progestins,besidehavingastrongprogestational without anyandrogenicorglucocorticoideffect.These were synthesizedwiththegoaloffindingamolecule Schoultz 1989,Camposet al.1999). them someundesirableandrogeniceffects(Nilsson&von They alsohavehighbindingaffinityfortheARconferring and LNGareexamplesofprogestinssecondgeneration. (Sitruk-Ware 2000).NET(alsoknownasnorethindrone) norethynodrel, oneofthefirstprogestinsynthesized (Stanczyk belong tothefirst-generationsyntheticprogestins which exhibitrelativelyhighaffinitytotheAR,generally DOI: 10.1530/JME-16-0061 http://jme.endocrinology-journals.org Review Review Review In contrast to PROG, which also shows an affinity for The findingthatprogestinscanalsointeractwith It is worthwhile to note that, since the relative However, no conclusivedataaboutaffinityof Over themorerecentdecades,newerprogestins 2013). Among these, there are MPA and et al. et al. 2003). t al.2006, et Pawlak et al. 1999, t al.2012).Progestins, et s

giatti © 2016SocietyforEndocrinology Philibert andothers Van Diepenet al. Zhu Printed inGreatBritain ). al.2011). et et al. 2003), et al. 1999, t al. et

3β,5α-reduced metabolite of this compound is able to 1997, to theAR,diminishesitsandrogenic potency(Lemus of NET, evenifconfersarelativelyhigh binding affinity tetrahydro-derivatives (Stanczyk2003 ). The5α-reduction and gestodene,resultsintheformationofdihydro- 5 andatthecarbonylgroupcarbon3,ofNET, LNG, and inturntheirtissue-specificeffects. availability for their cognate steroid hormone receptors progestins bytheAKR1Cenzymesmayinfluencetheir liver specific(Penning tissues withtheexceptionofAKR1C4,whichishighly reduction andaregenerallyexpressedindifferent catalyze 3-keto- and also 20-keto- and 17-keto-steroid 2000). Theseenzymesarepromiscuoussincetheycan et al. 1995),andAKR1C4(type1,3 α AKR1C3 (type 2, 3α 3, 3α dehydrogenase (HSD))(Hara and AKR1Cenzymes:AKR1C1(20α 2008, or AKR1D1(DiCostanzoet al. (AKR) superfamily. This includes steroid 5β process inhumansbelongtothealdo-ketoreductase remaining enzymesinvolvedinthetwo-stepreduction SRD5A2, andSRD5A3)(Azzouni steroid 5α similar mannerastheirparentalcompound.Apartfrom reductases andhydroxysteroiddehydrogenasesina progestins canbemetabolizedby5α prerequisite fortheprogestogenicactivity. Therefore, (∆4-3-ketone structure).These characteristics arethe carbon 3andadoublebondbetweencarbons45 PROG andtestosterone),containaketonegroupat Most ofprogestins,liketheirrelatedsteroids(i.e., Metabolism ofprogestins ( can resultincompoundsthathavedifferentactivities 2003) aswellbythemetabolismofprogestins,which globulin (SHBG))(Hammond2002, binding globulin(CBG),andsexhormone proteins thatbindsteroids(i.e.,albumin,corticosteroid- on theconcentrationandaffinityofplasmabinding endogenous competingsteroids.This,inturn,depends (free) fractionofboththecirculating progestinsand influenced byotherfactorssuchasthebioavailable The specificactionofdifferentprogestinsmayalsobe receptors in different cell types (Markov Progestins inthebrain Stanczyk 2003). Published byBioscientifica Ltd. Reduction atadoublebondbetweencarbons4and -HSD) (Deyashiki García-Becerra -reductase isozymefamily(e.g.,SRD5A1, -HSD and type 5, 17β 2002, et al. 2000).Themetabolismof et al. 1994, et al. Downloaded fromBioscientifica.com at10/01/202106:44:53AM et al. 1996),AKR1C2(type Moralí t al.2012),allthe et ,(3α -HSD) (Penning Dufort 57 57 Chen )-hydroxysteroid : : Schindler 2 2 2002).The et al. - or5β -HSD) (Khanna ). al. 2010). et ), 1996), et al. 2011) et al. -reductase -steroid R114 R114 t al. et et al. et al. via freeaccess

Journal of Molecular Endocrinology enzyme 3β-hydroxysteroiddehydrogenase-isomerase, and 3β-hydroxy metabolites.The former isgeneratedbythe isomer, suchas7α-methyl-NET, aswellthe3 α- and to otheractivemetabolites. These metabolites are Δ4- not convertedtotheprogestin NETbutitistransformed norethynodrel, however, incontrasttoitsprecursor, itis diacetate areprodrugsofNET. TIBisaderivativeof Among these,norethynodrel,lynestrenol,andethynodiol active metabolitesinordertoexertprogestationalactivity. Thus, theyrequireinvivobiochemicaltransformationto metabolism ofdydrogesterone. an involvementofcytochromeP450isozymesinthe Penning 2014).Recently, Olbrich 5β-pregnane and4-pregnenemetabolites(Rižner& transformed toseveralproductsincluding5α-pregnane, AKR enzymesonlyto20α-DHD,whereasprogesteroneis close instructuretoprogesterone,itismetabolizedby 2011, efficacy, whereasAKR1C3islessactive(Beranicˇ and AKR1C2canmetabolizedydrogesteronewithhigh al.2011).BothhumanAKR1Cisoforms,AKR1C1 et DHD) byhydrogenationofthe20-ketogroup(Beranicˇ metabolized intoitsactive20α-dihydrometabolite(20- after itsoraladministration,israpidlyabsorbedand progestogenic potencytothesecompounds. TMG into1β-and6-hydroxy-TMGmetabolitesconfers and hydroxylationatcarbons6(Stanczyket al.2013). (Stanczyk 2003).Indeed,MPA undergoesringAreduction steric hindranceduetotheacetategroupatcarbon17 way astherelatedsteroidPROG,probablybecauseof a ∆4-3-ketonestructure,isnotmetabolizedinthesame 2012). Ontheotherhand, although MPA alsopossesses exhibits stronganti-androgenicactivity(Rabe bond resultsintheformationof3α-hydroxy-CMA,which ofthe∆4-double of the3-ketogroupwithpreservation Like PROG,ithasa∆4-3-ketonestructure.Reduction together withMPA, isoneofthefirstPROGderivatives. inhibitor (Larreaet al.1987). CPA, a3β-hydroxysteroiddehydrogenase/Δ4,5isomerase the activityof5α-NETisinhibitedbytreatmentwith reduced theeffectof3β,5α-NETadministration,andthat that tamoxifen(i.e.,anestrogenbindingsitecompetitor) finding isinaccordancewithfurtherresults,showing et al. 2001, affinity islowerthanestradiol(Larrea activate genetranscriptionviaER,althoughitsbinding http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0061 Review Review Some oftheprogestinslack∆4-3-ketonestructure. The retroprogesteronederivativedydrogesterone, The hydroxylationofthe19-norpregnanederivatives The 17-hydroxyprogesteronederivativeCMA, 2012). Interestingly, althoughdydrogesteroneis Pasapera et al. 2002, Enríquez s

giatti © 2016SocietyforEndocrinology t al.(2016)showed et et al. 2001, andothers et al. 2007). This Printed inGreatBritain Santillán t al. et t al. et

to beclarified. exerted bythesemetabolites onGABA-Areceptorneeds 3 mentioned above, progestins are also converted in both clearly characterized(Bodine pathway forthislatterconversion,however, hasnotbeen ethinylestradiol (Wiegratz in lessamount,tothepotentestrogen7α-methyl- Penning 2014).Finally, TIBcanalsobemetabolized, receptor (Bäckström antagonize theeffectsofallopregnanoloneatGABA-A reduced metabolite(i.e.,isopregnanolone),can 2005). Ontheotherhand,conversionto3β conductance (Lambert in thepotentiationof GABA-induced chloride positive modulatorofGABA-Areceptorandresults intracellular steroidreceptors,butitisapotent hydroxyl groupatC3,doesnotinteractwithclassical 2008). This3α metabolism toallopregnanolone(Singh2007, multiple effectsonneuronsandglialcellsbylocal respectively (Stanczyket al.2013). as etonogestrel(alsocalled3-ketodesogestrel)andLNG, converted intheprogestationallyactivemetabolites,such is notinfluencedbythe7-methylgroup(Jinet al.2012). that thereductionof3-ketosteroidbyAKR1Cisoforms forTIBsuggesting stereochemical outcomeasobserved for lacking a methyl group at carbon 7, follows the same 2012). NorethynodrelwhichisidenticaltoTIBexcept dehydrogenase (Steckelbroeck stereospecificity withTIBactingasa3β-hydroxysteroid 3α-hydroxysteroid dehydrogenase,whereasitinvertsits 5α-dihydrotestosterone (5-DHT)behavingasanefficient Indeed, it produces 3α-products with the potent androgen preference dependingontheketosteroidsubstrate. Interestingly, AKR1C2exhibitsdifferentstereochemical major metaboliteintargettissues(Penning circulating metabolite,whereas3β-hydroxytiboloneisthe 2004). Thisexplainswhy3α-hydroxytiboloneisthemajor 3α-hydroxysteroid dehydrogenase (Steckelbroeck by AKR1C4whichfunctionspredominantlyas whereas inliver, TIBisreducedto3α-hydroxytibolone 3β-hydroxytibolone whichexhibitsestrogenicactivity, In peripheraltissues,AKR1C1andAKR1C2form depends onthetissuewhereitsmetabolismoccurs. activity. ConversionofTIBinto3α-orβ-hydroxytibolone exhibits amoderateandrogenicandprogestogenic 2002, Progestins inthebrain α Published byBioscientifica Ltd. ,5α It has been well established that PROG can exert Desogestrel andnorgestimate(NGM)arealsoprodrugs - and3β Dröge 2007, et al. ,5α ,5α -reduced metabolites,but the action -reduced metabolite,duetoa 2005, et al. Downloaded fromBioscientifica.com at10/01/202106:44:53AM t al.2003, et Zacharia t al.2002).Theenzymatic et t al.2002, et t al.2004, et Bitran 2007, et al. 57 Belelli &Lambert : 2 1991).As et al. Wiegratz t al.2014). et Rabe Rižner & Tsutsui R115 t al. et t al. et et al. ,5α via freeaccess -

Journal of Molecular Endocrinology pituitary, butonlyifadministeredincombinationwith content in hippocampus, hypothalamus and anterior 2007). AlsoCMAwasabletoincrease allopregnanolone by theadministrationofE2-V alone(Genazzani allopregnanolone levels.The sameeffectwasalsoobtained valerate (E2-V)wasabletoincreaseβ-endorphinand The concomitantadministrationofDRSPandestradiol affecting thereducedcontentofallopregnanolone. the levelsofβ-endorphin(Genazzani administered to ovariectomized rats, was able to increase (Genazzani increases allopregnanolonecontentintheadrenalgland andserum, whereasit as wellinanteriorpituitary frontal andparietallobes,hippocampus,hypothalamus, and allopregnanoloneinseveralbrainregions,such as Ovariectomy in Wistar rats reduces levels of significantly correlatedtohotflushes(Tepper been reportedinmenopausalwomen,andtheirdropis of theopioidreceptorexertinganalgesiceffects)have alterations ofthelevelsβ-endorphins(i.e.,ligands length andqualityofsleep(Gruber&Huber2003).Also of PROGtoperi-menopausalwomenpromotesthe evidence, indeed, suggested that the administration psychosocial behavior(Sator menopause arethoughttonegativelyinfluencewomen’s with GABA-Areceptor, andthereductionofitslevelsin above, thePROGmetaboliteallopregnanoloneinteracts allopregnanolone and β-endorphinlevels.Asmentioned compounds, alone orincombinationwith estrogens, on been usedtoexploretheeffectsofdifferentprogestin occurring in menopause. Indeed, this technique has experimental modelstomimicthehormonedrop Ovariectomy isasurgicalprocedurewidelyusedin Observations inanimalmodels replacement therapy(HRT). having combined oral contraceptive (COC) or hormone their neural effects in animal models and in women brain functions. Here, we discuss some data concerning little informationisavailableabouttheireffectson synthesized, with different characteristics. However, described, a plethora of progestin molecules have been function thatawomanwantstocontrol.Aspreviously progestin compoundassumedisrelatedtotheperipheral ages, ortolimitcomplicationsofmenopause.Thus,the functionsatyounger compounds inordertocontrolovary During lifetime, healthy women may assume progestin Effect ofprogestins in thenervous system DOI: 10.1530/JME-16-0061 http://jme.endocrinology-journals.org Review Review Review 2007).TheprogestinDRSP,et al. whenorally s t al.1999).Clinical et

giatti © 2016SocietyforEndocrinology et al. 2007),without andothers Printed inGreatBritain β-endorphins 1987). et al. t al. et

levels duringmenopause is thoughttodeeplyaffect neurotransmission andplasticity. Thedropinestrogens systemfor sustain theenergydemand ofthenervous functions (Rettberg system ofthebrain,acting alsoonmitochondrial (Genazzani et al.2007). effects, isabletopositivelyregulateβ-endorphinlevels of progestin, antimineralcorticoid, and anti-androgenic al.2004).Incontrast,DRSP, throughacombination et that couldinhibitthereleaseofβ-endorphins(Szot structure. Forexample,MPA hasaglucocorticoidactivity β-endorphin levels couldbesupposed based onprogestin (Bernardi ARK1C modulation mediated by the combined treatment allopregnanolone maybeaconsequenceofSRD5Aand 2006). Theauthorsproposedthattheincreasedlevelsof a greaterdegreerespecttoestrogenalone(Bernardi and,whenincombinationwithE2-V,anterior pituitary to and parietallobes,hypothalamus,hippocampus, able toincreaseallopregnanolonelevelsinthefrontal 2008). Finally, alsothefirst-generationmoleculeMPA was andplasma(Lenzi also intheanteriorpituitary combined withE2-V, β-endorphinlevelswereincreased hypothalamic levelsofβ-endorphin,whileonlywhen acetate (1 2008). Administrationofhighdosesnomegestrol allopregnanolone levelsinadrenalgland(Lenzi alone orincombinationwithE2-V, wasabletoreduce system.Indeed,administrationofthisprogestin, nervous 2008). This pattern of effects was a peculiarity of the (Lenzi the hypothalamusandanteriorpituitary induced an increase of allopregnanolone levels in both when nomegestrolacetatewasadministeredwithE2-V, it of allopregnanolonelevelsinhippocampus.However, progestin was administered alone, it induced an increase levels inovariectomizedrats.Inparticular, whenthis trol acetateinfluencesβ-endorphinandallopregnanolone (Lenzi pituitary allopregnanolone levelsinhippocampusandanterior combination with E2-V, possessed asynergisticeffect on levels inhippocampus,while,whenadministered administration wasabletoincreaseβ-endorphin combination withE2-V(Pluchino increased onlywhendydrogesteronewasadministeredin treatment wasineffectiveonβ-endorphinlevelsthatwere lobe, hippocampus, hypothalamus, and serum. This alone increasedallopregnanolonelevelsinfrontal E2-V (Pluchino Progestins inthebrain Published byBioscientifica Ltd. Estrogens exertbeneficialeffectsonthebioenergetics 2006 ). On the other hand, the effect on et al. mg/kg/day) alsoincreasedhippocampaland et al. 2009).Alsotreatmentwithnomeges­ t al.2009).Incontrast,dydrogesterone et t al.2014),whichisimportantto et Downloaded fromBioscientifica.com at10/01/202106:44:53AM 2008).Nestorone et al. 57 57 : : 2 2 R116 R116 t al. et t al. et t al. et et al. via freeaccess Journal of Molecular Endocrinology levels of the cortex, whereasLNG,alone or incombination,alteredthe expression oftheα1GABA-Areceptorsubunit in cerebral cerebral cortex.However, onlytheprogestin affectedthe PROG, andallopregnanolone inhippocampusand or theircombinationwereabletodecreasepregnenolone, The resultsobtainedsuggestthateitherEEorLNGalone combination ofEEandLNG,orwiththesinglemolecules. such alterations.Thus,femaleratsweretreatedwith a which componentofthepillwouldberesponsiblefor al.2002). A recentstudy addressed the question et and thus affecting anxiety behavior in female rats (Follesa composition, increasing the expression oftheγ2-subunit this combination was also able to alter GABA-A receptor Shively 2004).Moreover, long-termadministrationof 2 inmonkeys(Macacafascicularis),after was alsoobserved 2007, ( produced an increased Bax/Bcl-2 ratio, suggesting apoptosis exert similar effects. However, both MPA and LNG exerting also protective effects. In contrast, MPA did not increased ATP synthaseα-subunit(complexV)expression, particular, asPROG,LNG,andnestoronesignificantly progestins mayimpactmitochondrialfunctions.In and balancedbioenergetics(Irwin suggesting thatthesecompoundcouldpromoteefficient to areducedfreeradicalleakandlipidperoxidation, mitochondria inOVXrats.Theseeffectsarecoupled activityofbrain E2 areabletoincreasetherespiratory modulate mitochondrialfunctions.Indeed,PROGand after surgicalprocedure(Yao estrogen treatment,whenadministeredimmediately bioenergetics, aconditionthatcouldbereversedby agreement, OVX mice displayed decreased mitochondrial mitochondrial respirationandATP generation.In motivation (Follesa resulting inanimpairmentsocialbehaviorandsexual levels incerebralcortex,hippocampus,andplasma, reduced allopregnanolone, PROG, andpregnenolone (Simone female rats produced a decline in learning and memory & Gaitonde 1980). COC administration (EE in thehypothalamusandpons/medullaoblongata(Shetty pill producesadepletionofbiogenicaminesparticularly norgestrel revealedthattheprogestincomponentof a contraceptionpillcontainingethinylestradiol(EE)and models. For example, a study in female rats treated with replacement mayaffectbrainmitochondrialefficiency. Liu http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0061 years of treatment with EE and LNG (Henderson & Review Review Also theeffectofCOChasbeenexploredinanimal ). Overall, these data suggest that hormonal 2010).Overall,thesedatasuggestthathormonal et al. Santoru 2015).Inaddition,thesamecombination et al. γ2-subunit, increasing anxiety behavior in the t al.2014).Animpairedsocialbehavior et t al. 2002, et 2012).AlsoPROGcan et al. s

giatti 2008).Alsoother et al. Sassoè-Pognetto © 2016SocietyforEndocrinology andothers Printed inGreatBritain N) to + LNG) t al. et

of steroids(e.g.,star, produced alterationsinmanygenesrelatedtoproduction exposition tonorgestrelinzebrafisheleutheroembryos disturbing the circadian rhythm network (Zucchi 2015c). DRSPaffectscentralfunctionsinzebrafishbrain, intake ofiodideanionintothefollicularcells(Liang the sodium/iodidesymporterthatisresponsiblefor axis. Indeed,norgestrelinducedthegeneexpressionof to exertaneffectinthehypothalamic–pituitary–thyroid first stepofthesynthesisthyroidhormones,seemsalso and of steroidogenesis(Liang changes inthetranscriptionofgenesencodingenzymes due toalteredsexhormonelevels,asaconsequenceof females dependingonthedose.Thisshiftwasprobably withashiftinthesexratiotowardmalesor was observed, of juvenilezebrafish.Aninfluenceonsexdifferentiation (HPA)(HPG) andhypothalamic–pituitary–adrenal axes was evaluatedinthehypothalamic–pituitary–gonadal 2015a the exposition to MPA or dydrogesterone (Zhao inzebrafish(Daniorerio) afterfecundity wasobserved risk fortheaquaticwildlife.Forinstance,decreased sofarobtainedunderlinethe progestins. Observations environmental relevantconcentrationsofPROGor compounds onbrainfunctions,istheeffectof An emergingissue,concerningtheroleofthese Environmental effects inaquaticlife androgenic activityofLNG. possible explanationofthiseffectcouldbeascribedtothe ( whereas theexpressionofluteinizing hormoneβ the sex,LNGconcentration, andstageofdevelopment, β particular, theexpressionoffollicle-stimulating hormone disrupt thesexualdevelopmentalsoinXenopuslaevis.In if athigherdoses(Kroupova levels. Femaleswerealsoaffectedbythisprogestin,even expression ofgonadotrophinsandonthesexsteroid ), actingonthepituitary pubertal roach(Rutilusrutilus of LNG(31 2014, t al.2002, et able toaffectGABA-Areceptorcomposition(McIntyre but ratherduetoLNGcomponent.Sinceandrogensare not duetothereducedcontentofneuroactivesteroids, suggest thatchangesinGABA-Areceptorexpressionwere elevated plusmaze(Porcu Progestins inthebrain lhβ -subunit wasaffectedina specific wayinrelationto Published byBioscientifica Ltd. ) was reduced in both sexes (Lorenz Ar) (Liang ). Moreover, theeffectofnorgestrelexposure Zhao ng/L) affectsthereproductivesystemofmale 2015b et al. Henderson et al. 2015b cyp19a1a, cyp11b)ortheiractions(Pgr t al.2006, et ). Environmentalrelevantdoses Downloaded fromBioscientifica.com at10/01/202106:44:53AM et al. 2015a ). Thisprogestin,affectingthe 2012).Theseresultsmay et al. et al. 2014).LNGwasableto Jones ). Moreover, alsothe 57 : 2 t al.2006),a et t al. 2011a et -subunit R117 t al. et t al. et et al. via freeaccess ). ).

Journal of Molecular Endocrinology effect thatwasnotachieved byE2-Vtreatmentalone cortex; an andhigher-orderauditory in theprimary able toincreasethestimulus-induced corticalarousal task). DataindicatedthatE2-V discrimination oddball paradigm(i.e.,anauditory women weretestedwithLORETA duringatwo-tone 2005). Inanotherstudy, insomniacpostmenopausal cortices andintheanteriorcingulategyrus(Saletu in therightprefrontal,temporal,andsuperiorparietal this combination,butnotE2-Valone,increasedactivity resolution brainelectromagnetictomography(LORETA), accounting for daytime fatigue. As detected by low- was effectiveinimprovingthevigilancedecrement, 2009). However, DNG,whencombinedwithE2-V, younger postmenopausalwomen(Maki&Sundermann, estrogen treatmentalonewasbeneficial,butonlyin of Alzheimer’s disease(Marra decline inverbalmemory, whichisconsideredapredictor in postmenopausalwomenindependentlyoftheirage,a (Shumaker treated withconjugatedequineestrogen(CEE)andMPA of cognitivefunctionsinpostmenopausalwomen Study reported a decline Health Initiative (WHI) Memory Progestins ascomponentsofHRT study designs. doses, routes of administration, as well as the different in healthywomen,owingtothedifferentpreparations, to establishtheimpactofpharmacologicalregiments COC, needtobeelucidated.Inparticular, itisdifficult may also occurin brain of women on HRT or assuming in experimental models. However, whether these effects As depictedabove,progestinsmayalterbrainfunction Clinical observations compound. additional effectsinwomenalreadyassumingaprogestin contaminated drinkingwaterandseafood,withpossible humans, possiblyexposedtothesecompoundsvia This considerationmaysuggestpotentialactionson concentration foundinwatercouldaffectbrainfunctions. minnow (Pimephalespromelas) (Petersen significantly thoseofER to reduce,evenifnotsignificantly, thelevelsoflhβ arrest (Lorenz metamorphosis ofX.laevis,producingadevelopmental Moreover, LNGimpairedthyroidactivityduringthe DOI: 10.1530/JME-16-0061 http://jme.endocrinology-journals.org Review Review Review The reported observations highlightthatprogestins The reportedobservations 2003).Thesamecombination produced, et al. et al. 2011b ). NET(168 β

in brainoffemalefathead t al.2015).Incontrast, et + s

DNG combinationwas giatti © 2016SocietyforEndocrinology ± andothers 7.5 et al. 2015). Printed inGreatBritain ng/L) wasable The Women’s , and et al.

Choi been widelydemonstrated(Schneider&Farlow1997, has a directinfluenceofestrogenandPROGonmemory compared with placebo (Smith task, a higher activation of prefrontal cortex memory and NETacetateproduced,duringaspatialworking (Anderer inferior frontalgyri)ofCOC usersvsplacebocontrols left insula,middlefrontal gyrus,andbilateral lower emotional-induced reactivity inbrain(i.e., produced depressedmood, moodswings,fatigueand was reportedthattheadministrationofEEandLNG ofCOC-inducedadverse mood,it previous history other hand,inanotherstudyenrollingwomenwith was ineffectiveonmood(Rapkin healthy COC-naïvewomen,alow-dosecombination combination (Gingnell EEandLNG inwomenwhounderwent been observed only marginal effects in the response inhibition have situation seems to be more complicated. For instance, contraceptives Progestins ascomponentsoforal comprehension oftheleadingcauses(Barroset al.2015). develop dementia,thedataherediscussedmayhelp estrogen–progestin regimenscouldincreasetheriskto of HRT. Since the WHI studyreported that combined 2012). Theseresultsarealsorelevantinthecontext insulin signalingandcholesteroltrafficking(Zhao involved in mitochondrial energy, redox homeostasis, cyclic PROGtreatmentimprovedtheexpressionofgene Incontrast,inthesamemodel,E2and were observed. and ratsadministeredwithE2continuousPROG rats, nodifferencesbetweenvehicle-treatedanimals different effects.Forexample,inhippocampusofOVX Indeed, continuousvscyclicadministrationmayproduce also thescheduleofPROGtreatmentcouldberelevant. training). Moreover, as suggested by animal models, exposure before learning vs acuteadministration after is dependent on the time of administration (e.g., chronic 2015)suggestthattheeffectofPROGonmemory et al. disrupt this effect. However, (Barros recent observations in animalmodels(Bimonte-Nelson women withAlzheimer’s disease(Honjo positive actiononmemory, PROGadministrationto PROG. Forexample,whileestrogenseemstoexerta resultshavebeensofarobtainedabout contradictory processes havenotbeenyetfullyidentified.Inparticular, 2006). However, themechanismsinvolvedinthese Progestins inthebrain Published byBioscientifica Ltd. 2003, et al. t al.2004 ). Moreover, thecombinationofEE et Bimonte-Nelson In womenassumingCOC,the Downloaded fromBioscientifica.com at10/01/202106:44:53AM t al.2016).Inaddition,in et 2006). Furthermore, et al. 2004, et al. t al.2006).Onthe et 2006)seemsto et al. 57 57 : : 2 2 2005)and et al. Walf R118 R118 t al. et et al. via freeaccess

Journal of Molecular Endocrinology mood swings(Paoletti DRSP orchlormadinonewereabletoreduceanxietyand Paoletti plasma levelsof allopregnanolone (Follesa Furthermore, differentcombinationsofCOCdecreased subdermal implantofLNG(Wagner &Berenson1994). anxiety andmooddisordersafteralong-acting ofdepression,reportedincreased no previoushistory ( ( reportednochanges 2013), whileotherobservations has beenidentifiedinCOCusersvsnonusers(Gogos particular, task abetterperformanceinverbalmemory been evaluatedbetweenCOCusersandnonusers.In Possible differencesincognitiveperformanceshavealso and attention(Rosenberg&Park2002, reported nodifferencesinspatialability, verbalfluency, with nonusers.Onthecontrary, otherobservations 2008, et al. also inverbalfluencyandmentalrotation(Wharton Holloway outperform inassociativelearning(Beck 2015, and trauma(Melcangi&Garcia-Segura 2010, effects exertedbyPROGin models ofneurodegeneration Recently, it has been proposed that some of the protective Protective effects ofprogestins inthebrain non-COC users(Pletzer with anandrogenicprogestincomponentinthepilland in thefacerecognitiontestwithrespecttoCOCusers reported. Thiswasaccompaniedbyabetterperformance of womenassuminganonandrogenicprogestinwasalso in theparahippocampalandfusiformgyricerebellum potency of the progestin compound. An increased volume users dependingontheandrogenicvsnonandrogenic recognition performancearedifferentiallyaffectedinCOC recently reportedthatfrontalgraymattervolumeandface 2014, imaging studies(Gogos of COC in humanbrainhavealsobeen obtained by Mordecai consequent cognitiveskills.Indeed,Pletzer compound intothepillmayaffectbrainanatomyand 2014).Forinstance,the‘androgenicity’ofprogestin et al. little attentioninthestudiesperformedsofar(Toffoletto of progestincomponentintoCOC,anissuethatreceived be duetothemolecularstructureandspecificgeneration Gingnell Islam http://jme.endocrinology-journals.org DOI: 10.1530/JME-16-0061 Review Review As recently emerged, discordant results on the effects As recentlyemerged,discordantresultsontheeffects Melcangi Toffoletto t al.2008, et 2004, et al. et al. 2008, 2013).Moreover, healthywomen,with et al. 2011),andbetterresultswereobtained et al. Griksiene &Ruksenas2011)whencompared et al. 2015 ) couldalsobeachievedthrough ). A possible explanation may 2014).Apossibleexplanationmay et al. Rapkin Mihalik Nielsen et al. 2015). 2014, et al. t al.2004, et 2006).Onthecontrary,et al. et al. 2011, t al.2009).COCusers et s

giatti © 2016SocietyforEndocrinology Pletzer & Kerschbaum Pletzer &Kerschbaum Huber andothers Islam Gogos 2013). Printed inGreatBritain ). al.2008). et t al.2008, et t al.(2015) et t al. 2002, et Giatti et al. 2008, et al.

regiment, doesnotexertprotective effects. one ofthemostprescribed progestin compound inHRT rotarod, comparedwithvehicle animals(Liuet al.2012). and increasing the time spent by lesioned mice on the effects similartoPROG,reducingthetotalinfarct volume occlusionmice),nestoroneexerted neuroprotective artery animals (Hussainet al.2011). inslicesfrom PGRknockout effects werenotobserved its interactionwiththeintracellularPGR,becausethese cells. Theeffectsexertedbynestoroneareprobablydue to recruitment andmaturationofoligodendrocytesprecursor oligodendrocytes, throughamechanisminvolving was abletopromotetheremyelinationofneuronsby rodents, treated with lysolecitin. The synthetic progestin organotypic culturesofcerebellarslicesfrompostnatal myelin-promoting effectsofnestoronewereevaluatedin in thisexperimentalmodel(El-Etr precursor andmatureoligodendrocyteswasalsoobserved and proteolipidprotein),increaseddensityofboth important myelinproteins(i.e.,basicprotein microglial activation.Anincreasedexpressionoftwo presented, tonearlythesameextent,lessastrocyteand fed with cuprizone and injected with PROG or nestorone GABAergic interneurons(Garay positive neuroblastinthesamebrain region, increasingalso promote cell proliferation and double-immunocortin- microglial reactivityinhippocampus,anditwasableto this experimentalmodel,progestinalsodecreased and increasedthemotorbehaviorinaffectedanimals.In nestorone was able to decrease the neurological disability demyelination models.Inparticular, inEAEmice, mice, thecuprizonefeeding,andlysolecitin-induced different modelsofmultiplesclerosis,suchastheEAE effectswerealsoobtainedinthree and anti-inflammatory synthase, andNF-κB(Meyer function-associated antigen 1,TNF-α,induciblenitricoxide and theexpressionofmicroglialmarkerlymphocyte (NF-κB) inhibitorexpression,whiledecreasedastrogliosis of kappalightpolypeptidegeneenhancerinB-cells acetyltransferase, glutaminesynthase,andnuclearfactor typical ofthepathology. Moreover, itincreasedcholine- digitsinforelimbs, abnormalities andinvertedthecurved nestorone administrationrestoredthespinalcord mice, amodelforprogressivemotoneurondegeneration, test possibleneuroprotectiveeffects.Inthewobblermutant agonist) wasstudiedindifferentexperimentalmodelsto nestorone. Inparticular, thisprogestin(i.e.,apotentPGR the administrationofaprogestincompound,suchas Progestins inthebrain Published byBioscientifica Ltd. In contrast to what is observed withnestorone,MPA,In contrasttowhatisobserved Also in a model of ischemia (i.e., the middle cerebral Downloaded fromBioscientifica.com at10/01/202106:44:53AM 2015).Neuroprotective et al. 2014).Femalemice et al. et al. 2015).Finally, the 57 : 2 R119 via freeaccess

Journal of Molecular Endocrinology MPA wasineffectiveincontrastingtheCa factors, suchasB-celllymphoma2(BCL2).Incontrast, the promotionoftranscriptionanti-apoptotic of extracellularsignal-regulatedkinasesignalingand influx mediatedbyglutamate,throughtheactivation cultures, PROGwasprotectivebyreducingtheCa effect(Jodhka an inhibitory of thebrain-derivedneutrophicfactor, whileMPA exerted explants, PROGincreasedexpressionandproteinlevels protective effects. For instance, in cerebral cortical neurodegenerative models,PROG,butnotMPA, exerts higher affinity(Koubovec bind ARandGR(Schindler can bindtoPGR, but MPA, unlike PROG, is also ableto mechanism ofactiononbrain.Indeed,bothsteroids estrogen treatment,theyareprofoundlydifferentintheir in preventingtheuterotrophiceffectsofunopposed suggest that,evenifPROGandMPA arenearlyidentical sofarobtained Stanczyk &Bhavnani2015).Observations animal modelsandHRTpatients(Singh&Su2013, results ofPROGvsMPA administrationindifferent 2002).Inaddition,manystudiesreportconflicting et al. embolism intheCEE cancer, heart disease, stroke, and pulmonary coronary brain functionshavebeenlittle explored.Inrecentyears, clinical useofthese molecules, theirpossibleeffects on with high affinity for PGR. However, despite the large stimulated theproduction of newmolecules,possibly increasing interestandrequest forefficientcompounds Since thesynthesisoffirstprogestinin1938, Conclusions ( possibly blockingprogesteroneneuroprotectiveeffects the inhibition of ARK1C ezyme (Khanim conversion ofPROGintoallopregnanolone,through it hasbeenreportedthatMPA couldantagonizethe ( metabolites, such asDHPand allopregnanolone seem tobemediatedbyitsconversionintoneuroactive al.2011).ManyneuroprotectiveeffectsofPROG et activity, suggestingmitochondrialimpairment(Irwin protein and in glycolytic and oxidative phosphorylation in brain,OVXratstreatedwithMPA showedadecline glycolysis, oxidativestress,andmitochondrialfunction ( the protectiveactionofestradiol,whenco-administered not promotethetranscriptionofBCL2andinhibited Stanczyk &Bhavnani2015). Melcangi Nilsen &Brinton2002, DOI: 10.1530/JME-16-0061 http://jme.endocrinology-journals.org Review Review Review WHI resultsreportedanincreasedriskforbreast t al.2014, et +

Giatti MPA armofthestudy(Rossouw 2003). Similarly, whentestedfor t al.2005).Inexperimental et 2009).Inhippocampal et al. 2003)witha300-fold et al. t al.2015).Interestingly, et s

giatti © 2016SocietyforEndocrinology andothers Printed inGreatBritain 2 + ), al. 2014), et influx,did 2 +

to dissectthisintriguingandfascinatingfieldofresearch. and new animal and human studies performed, in order For thesereasons,rigorousguidelinesshouldbeproposed, also progestincompoundsareexposedtothesamefate. brain aredeeplylinkedtoitsmetabolism,and,possibly, should be further explored because the effects of PROG in as by their metabolism. In particular, this latter aspect such astheinteractionwithdifferentreceptorswell ignored, is represented by their mechanism of action, Furthermore, anotherlevelofcomplication,highly just to cite some, increased the complexity of this field. baseline hormonalstatus,andageoftreatedwomen, dose, durationofexposure,androuteadministration, studies. Moreover, allthecombinationsintermsof produced confoundingresults,inparticularhuman and fewattentionofthemoleculesassumedmayhave different study designs knowledge, even though very preclinical andclinicalstudiestriedtofillthisgapof Azzouni F, Godoy A, Li Y & Mohler J 2012 The 5 alpha-reductase isozyme 2012The5alpha-reductaseisozyme &Mohler J Azzouni F, Li Y Godoy A, & Huber J Metka M, Gruber D, Anderer P, Saletu-Zyhlarz G, Saletu B, 2011Molecularmechanismsof &Hapgood JP Verhoog N Africander D, References to RCM(grantnumber2012-0547). The authorsacknowledgefinancialsupportfromtheFondazioneCariplo Funding perceived asprejudicingtheimpartialityofthisreview. The authorsdeclarethatthereisnoconflictofinterestcouldbe Declaration ofinterest Barbaccia ML, Serra M, Purdy RH & Biggio G 2001Stressand &Biggio G Purdy RH Serra M, Barbaccia ML, 1980 InhibitionofthedailyLHrelease &Freeman ME Banks JA 1999 &Schulte HM Beil FU Else T, Bamberger AM, Bamberger CM, Bäckström T, &Wang MD Wahlström G,2005 Wahlström K, Zhu D Progestins inthebrain Published byBioscientifica Ltd. Advances inUrology family: areviewofbasicbiologyandtheirroleinhumandiseases. 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