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European Journal of Endocrinology -18-0378 so in the early 1970s. It was at this exciting time in so intheearly1970s.Itwasatthisexcitingtime in in therapyofendocrineandneurologicaldiseases.Not questions theimportanceofdopamineagonistdrugs mesylate, (CB154) bromocriptine ( It is 50 years of 2-Br- since the discovery Introduction discovered. by work, Stollandhisteamwereleadersinidentifyingthestructureofmanyotheralkaloidsaminesproduced in 1918andwastranslatedintoapharmaceuticalproduct1921underthetradenameGynergen.Insubsequent active principleofanoldpopularremedyforexcessivepost-partumbleeding.Thesuccessthisdiscoveryoccurred started hisindustrialresearchworkwithergot.Hesucceededinisolating,fromtheergotofrye,ergotamineas an Chemical Company. Stoll,using the specialmethodsofextractionlearnedfromhisworkwithmentorWillstetter, home toSwitzerlandfromGermany, toleadthedevelopmentofanewpharmaceuticaldepartmentatSandoz the MonksofSt.Anthonywhowereparticularlyskilledattreatingcondition.In1917,Prof.ArthurStollreturned manifestations. IntheMiddleAges,gangrenouspoisoningwasknownasSt.Anthony’s fire,aftertheorderof purpurea Ergotism isthelong-termergotpoisoningbyingestionofryeorothergrainsinfectedwithfungus Abstract Oregon, USA,and 1 G Michael Besser 50 years sincethediscoveryofbromocriptine ANNIVERSARY REVIEW Medicine, StBartholomew’s Hospital,London,UK, https://doi.org/ www.ej Review Review Medal oftheSocietyforEndocrinology Society EdwinB.Astwood,Distinguished PhysicianandFredConradKochAwards, andtheDale American CollegeofPhysicians (ACP),andreceivedACPJohnPhillipsMemorialAward, Endocrine hormone secretagogues.Hehas beenmadeFellow, AmericanAcademyofArts andSciences,Master, has been thedecline of growthhormone secretion during aging and itsreversibilitywith growth drugs, and identification of pancreatic tumor ina patient with acromegaly. Hisresearch interest tumorscanbetreatedwithdopamineagonist demonstration thatprolactin-secretingpituitary physiologyandpathophysiology.hypothalamic pituitary Hiscontributionsincludethe Michael OThorner, Invited Author’s profile Claviceps purpurea e-online.org andmorerecentlybyexcessiveintakeofergotdrugs.Ithaseitherneuropsychiatricorvascular 10.1530/EJE 3 Medicine, UniversityofVirginia,Charlottesville,USA 1 -18-0378 , Ronald F Pfeiffer . Thiswastheculturalbackgroundandscientificfoundationonwhichbromocriptine

2 Emeritus ProfessorofMedicine,UniversityVirginia, hasstudied © 2018EuropeanSociety ofEndocrinology others G MichaelBesserand α 1 -bromoergokryptine -bromoergokryptine ). Today, no one 2 and 2 Neurology, OregonHealth&ScienceUniversity, Portland, . Printed inGreatBritain Michael O Thorner and perseveranceofitsfounder, Prof.EdwardFlückiger. asitisquiteremarkableandreflects thewisdom discovery ofbromocriptine’sin man.Itisworthrecountingthestory being identified,isolatedandsequencedthenstudied neuroendocrinology that thehypothalamichormoneswere bromocriptine Dopamine agonists: Published byBioscientifica Ltd. 3 Downloaded fromBioscientifica.com at09/28/202109:59:47PM (2018) Endocrinology European Journal of [email protected] Email to MOThorner should beaddressed Correspondence 179 179 :2 , R69–R75 Claviceps

R69 –R75 via freeaccess European Journal of Endocrinology www.eje-online.org twist in the story wasthatbromocriptinedeveloped twist inthestory fertility inpatientswithhyperprolactinemia. Thenext is notluteotrophicandsuppression ofprolactinrestores prolactin has different roles in humans than in the rat. It ovum orblockingpseudopregnancy. We nowknowthat lactation, inhibition of implantation of the fertilized the prolactinactivitiesinhisrats–suppression of Flückiger hadtorelyon measurement ofeitherGHorprolactin.Thus,Prof. have acromegaly. others withgalactorrheaandhypogonadismwhodidnot acromegalic patientswhodidnothavegalactorrhea or as aseparatehormonecouldnotexplainthemany prolactin receptors.However, thedenialofexistence GH andprolactinareequallyeffectiveinstimulating could beexplainedbygrowthhormone(GH).Both the humanandalllactogenicactioninblood hormones, hadstatedthatprolactindidnotexistin previously for isolating somany purified pituitary that attimeCHLi,whohadbeenresponsible be approvedfortreatmentofpatients. he madeandwhichbecamethefirstdopamineagonistto vascular effects. Bromocriptine was the compound which the prolactin-loweringactionwithoutoxytocicor He therefore set out to modify its structure and bring out in humans due to its oxytocic and vascular effects ( implantation ofthefertilizedovum( for sustainingtheproductionofprogesterone suppressed prolactinandthatwasresponsible and remarkablestudies,heidentifiedthatergocornine studying ratphysiologyandthroughaseriesoflogical of thefertilizedovuminendometrium( understand themechanismsunderlyingimplantation it asaninvestigativepharmacologicalprobetohelp these effects were mediated by ergocornine and used had ananti-fertilityeffect( prevented implantationofthefertilizedovumandthus progresterone productionbythecorpusluteumit interfered with early gestation in the rat by preventing of deciduomatainpseudopregnantratsandalso andergocristine,inhibitedtheformation ergocryptine extract knownasergotoxine,amixtureofergocornine, published thefirstpapershowingthatergot at theWeitzman InstituteinIsrael.In1954,Shelesnyak of Shelesnyak who was an American scientist working which isnowNovartis.Hesetouttobuildonthework Review No immunoassayswereavailableatthattimefor isevenmoreremarkablewhenconsidering The story Flückiger realizedthatergocorninecouldnotbeused Prof. FlückigerwasworkingatSandozPharmaceuticals, in vivo 2 , 3 bioassayswhenstudying ). Hedemonstratedthat others G MichaelBesserand 4 , 5 ). 4 ). Hewas 6 ). that thislactogenicactivitycouldnot be blockedby low,in whomGHlevelswerevery andthatfurther existed inthe circulation of patients with galactorrhea able toshowthatprolactin-likelactogenicbioactivity culture (frommiceandrabbitsrespectively)were pigeon cropassay, theyusedbreasttissueinorgan insensitivesensitive bioassays.Insteadofusingthevery separately inthehuman.Theydevelopednewmore finally demonstratedthatprolactinandGHexisted New York andSt.Bartholomew’s HospitalinLondon and their respective colleagues at Columbia University, who madethem.AndrewFrantzandMichaelBesser andtheinvestigatorsto someofthekeyobservations of awholearticlesoherewewouldjustliketopoint prolactin secretion. orbromocriptinesuppressed unknown howergocryptine Dopamine receptors had not yet been identified and itwas as aninhibitorofprolactinsecretioninthehuman. was that all hypothalamic regulatory hormoneswouldbe was thatallhypothalamicregulatory like substance as the conventional wisdom at that time inhibiting factormightbe related toacatecholamine- battle in suggesting that the hypothalamic prolactin- D2 dopaminereceptors.MacLeod wasfightinganuphill were newreceptorsinvolved.Theselatershowntobe blocked by these neuroleptic drugs, suggesting that there Similarly, couldbe effect ofergocryptine theinhibitory but wasblockedbyphenothiazinesandhaloperidol. effectwasnotblockedbyalpha orbetablockade secretory norepinephrine anddopamine( synthesis/secretion wassuppressedbyepinephrine, a bandongelelectrophoresisandshowedthatprolactin term culture.Hewasmeasuringprolactinatthattimefrom control ofprolactinreleasefromhemipituitariesinshort- MacLeod at the University of Virginia was studying the performed byEmiliodelPozoinSwitzerland( ( been presentformanyyears.Theeffectwasdramatic and potencyreturnedevenifthehypogonadismhad reversal of the patients’ hypogonadism. Menstruation circulating prolactin levels and resulted in immediate or bromoergocriptine) rapidly lowered the elevated demonstrated thatbromocriptine(thenknownasCB154 had beenshowntohavehyperprolactinemia.They with inappropriatelactationandhypogonadismwho bromocriptine; theydidsoinmaleandfemalepatients then allowedtoperformclinicalstudieswith Bartholomew’s Hospitalwerethefirstinvestigators specific anti-GHantisera( bromocriptine Dopamine agonists: 10 ). Similarstudies confirming theseeffectswere Each oneofthesestatementscouldbethesubject As theseclinicalstudieswereunderway, Robert Downloaded fromBioscientifica.com at09/28/202109:59:47PM 7 , 8 , 13 9 ). However, theanti- ). ThegroupatSt. 179 :2 11 , 12 R70 ). via freeaccess European Journal of Endocrinology patients with pituitary macroadenomaswhohadbeen patients withpituitary Tindall tumorswere collectedfrom inAtlanta,pituitary collaboration withKalmanKovacs inToronto andGeorge tumor was shown to have reduced in size ( began toimprove( headache improvedandbyday3,hisvisualfieldsalso following thefirstdoseofbromocriptine,hiscatastrophic Investigation Committee, thepatient was admittedand Following receiving appropriate approval fromthe Human offered experimental medical treatment asaninpatient. – attemptedremoval.Thispatientrefusedandhewas tumorswas neurosurgical patients withlargepituitary hypogonadism. Thestandardofcareatthattimeinsuch tumor, severe visualfielddefects,severeheadachesand largepituitary to bereferredayoungmanwithvery fortunate when he arrived at the University of Virginia rarely normalized the prolactin. Michael Thorner was transsphenoidal ortransfrontalsurgery. Thesetherapies radiationtherapyor many patientshadpituitary tumorsizeandtherefore had aneffectonthepituitary therapy. Initially, itwasunclear whether bromocriptine impotence whicharereversedwithbromocriptine Men withhyperprolactinemiahavelackoflibidoand serum prolactincouldeasilydiagnosehyperprolactinemia. a oligomenorrhea andlutealdysfunction.Measurementof menstrual dysfunctionrangingfromamenorrheato function ( with bromocriptine withrestorationofnormalgonadal tumors andhyperprolactinemiareliablycouldbetreated women withmenstrual dysfunction who harbored small and approximately50%ofthemareprolactinomas.In disorder. We tumorsarecommon knowthatpituitary became themostcommonhypothalamic/pituitary as physicians became aware of its existence and it diagnosis ofhyperprolactinemiaincreaseddramatically hyperprolactinemia wasrapidlyacknowledged.The secretion ( inhibiting hormonewhichtonicallysuppressesprolactin generally acceptedthatdopamineistheprolactin- dopamine wasisolatedfromportalbloodanditbecame ( with bromocriptinereduceddopamineturnover into the hypothalamus and that treatment of a rat turnover wasincreasedwhenprolactininjected and FuxeinStockholmdemonstratedthatdopamine Canada ultimatelyisolatedprolactin( hormone wasdopaminecontroversial( peptides. Thus,tosuggestthattheprolactin-inhibiting 15 Review ). AllthissupportedMacLeod’s hypothesis.Later, The efficacyofbromocriptineintreating FriesenandhiscolleaguesinWinnipegHenry in 16 10 , ). 12 , 17 i. 1 Fig. ). Their prior dysfunction included ) and by 2 weeks, his pituitary weeks,hispituitary ) andby2 others G MichaelBesserand 13 14 18 ). ). Corrodi ). Later, in object. ReproducedwithpermissionfromThorner superior bitemporalquadranticdefecttothelow-intensity noted; theonlyabnormalityat6 monthswasanequivocal Thereafter, progressiveimprovementinthevisualfieldswas had improved,andvisualacuitywasrestoredto20/20. reduced visualacuityinboth.After3 days,theleftfield incomplete hemianopsiaintherighteyewerepresent,with a completetemporalhemianopsiainthelefteyeandan indicates anormalvisualfieldforcomparison.Beforetherapy, apostilb (Li)and100(I2).Theblackperiphery 0.25 mm Goldman apparatusunderidenticalconditionswitha The visualfieldswereplottedbyoneobserverusingthe plots beforeandduring6 monthsofbromocriptinetherapy. Visual acuityanddiagrammaticrepresentationofvisualfield Figure 1 functioning tumors( were reduced20fold,butthis didnotoccurinthe‘non’- cells demonstratedthatthe volumeofthetumorcells prior to surgery. The treated prolactin for tumor 6 weeks bromocriptine Dopamine agonists: 2 objectattwodifferent lightintensities,1000 19 ). Further, iftreatmentwasstopped Downloaded fromBioscientifica.com at09/28/202109:59:47PM 179 www.eje-online.org :2 et al . ( R71 18 ). via freeaccess European Journal of Endocrinology www.eje-online.org effects, butCalneandcolleagues foundthatbromocriptine piribedil ( two earlierdopamine agonists, apomorphine ( bromocriptine inpatients with PD.Clinicaltrials National Institutes of Health in Bethesda, to evaluate at HammersmithHospitalinLondonandlaterthe agonist led Donald Calne and his colleagues, initially sorely needed. it becameobviousthatmoreeffectivetreatmentwasstill appeared in many individuals treated with levodopa and movements, typically choreiform in character, also dose oflevodopabecameprogressivelyshorter. Dyskinetic in motorresponse,whichthedurationofefficacy a to levodopafrequentlybecamemarredbyfluctuations became clearthatsuchwasnotthecase.Theresponse for thedisorder. With the passage oftime,however, it and raisedhopesthatlevodopamightevenbeacure ( revolutionized the treatmentof Parkinson’s disease(PD) The introduction of levodopa in the 1960s had colleagues ( agonist in acromegaly. This was reviewed by Giustina and is thedrugofchoicetodayfortreatmentbyadopamine elevation ofGHlevels.Asinprolactinomas, cabergoline it canbeeffectiveparticularlyinpatientswithmild doses are required than are needed in hyperprolactinemia, used. However, itisanoraltherapyandalthoughhigher receptor antagonistpegvisomant,DAagonistsbecameless somatostatin analogs were introduced followed by the GH ring size was reduced ( hyperhidrosis, jointpainandswellingofthedigitssothat importantly relievedmanyofthesymptomsincluding and IGF-Ilevelsinmostbutnotallpatients not aseffectiveinprolactinomas,butitdidlowerGH performed studies in patients with acromegaly. It was Bartholomew’s HospitalinLondonandtheItaliangroup acromegaly ( surprising andparadoxicalsuppressioninpatientswith GH secretioninnormalsubjects.However, therewasa colleagues inItalyhadidentifiedthatL-Dopastimulated it canbeadministeredonceortwiceperweek. preferred drugduetoitslongdurationofactionsuchthat and isreviewedbyMolitch( agonists isestablishedinpatientswithprolactinomas of bromocriptineandthelaterdevelopeddopamine and thuslong-termtherapywasrequired( after ayearoftreatment,thetumorcouldre-expand 29 Review ). The initial response to levodopa often was dramatic The knowledge that bromocriptine was a dopamine Parkinson’s disease( In his studies on GH secretion, Liuzzi and his 31 27 ), hadbeendisappointing due toadverse 22 ). ). SeveralgroupsincludingthoseatSt. 23 28 , 24 ) andneurologicalindications: 21 , 25 ). Today, cabergolineisthe , others G MichaelBesserand 26 ). As the more active 20 ). Therole 30 ) and dopaminergic functionwasemerging,culminatinginthe another landmarkadvanceintheunderstandingof dopamine agonists in the treatment of PDwasunfolding, newer dopamineagonists. soon ledtothedevelopmentofanexpandingarraystill adequately tolevodopa.Thesuccessofbromocriptine effective eveninpatientswhowerenolongerresponding to openthepossibilitythatbromocriptinemightbe stimulates dopaminereceptorswasalsoconsidered be convertedtodopaminebydopadecarboxylase, directly The factthatbromocriptine,unlikelevodopawhichmust which theydesignatedD1andD2( there aretwodistinctcategoriesofdopaminereceptor, proposal in1979byJohnKebabianandDonaldCalnethat comparable tolevodopacouldbeachieved( levodopa andthatathigherdoses,atherapeuticeffect as monotherapyandwhenusedinconjunctionwith doses upto100 ( tolerated andprovidedimprovementinmotorfunction at dosesupto30 agonists asalevodopa-sparing treatmentstrategywas The concept of using bromocriptine and other dopamine to dopamineneuronsbymeans offreeradicalproduction. agonists andsuggestedthat levodopaitselfmaybetoxic risk ofdeveloping motor fluctuations withdopamine favoring dopamineagonistsfocusedonthereduced lower likelihoodofproducing psychiatric toxicity; those favoring levodopapointedtoitssuperiorefficacyand with adopamineagonistsuchasbromocriptine.Those whether PDtreatmentshouldbeginwithlevodopa or these years,controversyswirledaroundthequestion of dopamine receptor agonists was not achieved. During gauntlet tohumanuse.Thepromiseofpreciselyselective D1 receptor agonist ever passed the pharmacological unfortunate and perhaps surprising that no selective family, withsomevariabilityinsubtypeselectivity. Itis Like bromocriptine,allwereselectivefortheD2receptor lisuride, pergolide, mesulergine, cabergoline and others. dopamine agonists,withtheintroductionoflergotrile, effective andlesslikelytoproduceadverseeffects. receptors couldbediscoveredthatwouldevenmore that dopamineagonistsselectiveforstriatal the search for additional dopamine agonists, with the hope receptor families described earlier ( the fivecouldstillbeplacedwithintwodopamine expanded thenumberofdopaminereceptorstofive,but research utilizingmolecular biologicaltechniques bromocriptine Dopamine agonists: 32 ). Subsequentstudiesreportedthatbromocriptinein As thepotentialroleforbromocriptineandother The 1980sand1990swereaneraofproliferation mg dailyprovidedimprovementboth mg daily, whenaddedtolevodopa,was Downloaded fromBioscientifica.com at09/28/202109:59:47PM 37 ). This further fueled 179 :2 36 ). Subsequent 28 , 33

34 R72 , 35 via freeaccess ). European Journal of Endocrinology LLC, Tiverton, RI.ReproducedwithPermission fromAnthonyCincotta,VeroScience LLC. Parlodel (packageinsert).Suffern, NY, andEastHanover, NJ;Novartis PharmaceuticalsCorporation,2006;CyclosetPackageInsert2016;and VeroScience Approved indication Elimination halflife Time tomaximumplasmalevel Unabsorbed dose Bioavailability (absorbeddose) Bromocriptine form Table 1 bromocriptine haslargelypassedfromthePDtreatment both forPDandrestlesslegssyndrome.Although an importantplaceinthetreatmentarmamentarium, for theuseofdopamineagonists,although they stillretain in more recent years has further tempered the enthusiasm such asexcessivesleepinessandimpulsecontroldisorders, for PD.Therecognitionofothertreatmentcomplications, dopamine agonist therapy bromocriptine as the primary use intheUSA1997,ledtoagradualabandonmentof ropinirole orpramipexole,whichhadbeenapprovedfor by usingoneofthenon-ergotdopamineagonistssuchas discontinuation of the offending drug, could be avoided of therapy, althoughoftenreversiblefollowing during theday. Therecognitionthatthesecomplications at dosesorabove20 retroperitoneal fibrosis also were reported predominantly ( treated withbromocriptinewasintherangeof2–5% changes in individualswithPD of pleuropulmonary McElvaney and colleagues suggested that the prevalence a growingnumberofreportedcasessurfacedandin1988, reported byRinnein1981( prolonged administration of bromocriptine was first changesinPDpatientsfollowing of pleuropulmonary traced totheergotpropertiesofdrugs.Theappearance 1980s, someadverseeffectsbegantoappearthatcouldbe dose bromocriptine therapy in the treatment of PD in the ergot derivatives,andwiththeincreasinguseofhigh- agonists (bromocriptine,pergolide,cabergoline)were used inthetreatmentofPD.Severaldopamine dopamineagonist of bromocriptine as theprimary it wasoneimportantdifferencethatledtothedemise differences between the various dopamine agonists and placed torest. what waslabeledbysomeas“levodopaphobia”( that theideaoflevodopatoxicitywasdisproven( popularized and it was not untila number of years later 41 Review ). Constrictive pericarditis, valvular heart diseaseand It isnotcorrecttosay, however, thattherewereno Comparison ofkeybioavailabilitycharacteristicsCyclosetand Parlodel.

mg/day whendosedmultipletimes 40 ). Overthenextseveralyears, Glycemic control 6 h 53 min 5–25% 65–95% Micronized tospecificparticlesizedistribution Cycloset generate specificdissolutionprofile others G MichaelBesserand

38 39 ) and ) was of 1.6–4.8 promise but has not been widely adopted as yet. At doses is describedbydeFronzo( and haveashorterdurationofaction( 2 which isdosedonlyoncedailyinthemorningwithin or acromegaly. Thisisforanewformulation(Cycloset) than used for the treatment of PD or hyperprolactinemia mellitus type2(T2DM)atdosagesgenerallymuchless bromocriptine wasapprovedforthetreatmentofdiabetes that timeandwhereitwasbeingresearched ( wrote amonographwhichdiscussedthestateofartat Prof. Flückiger, Donald Calne and Thorner first 10 years, been usedformultipleotherindicationsandafterthe tumors,acromegalyandPD.Ithas including pituitary treatment of hyperprolactinemia-associated dysfunctions agonist firstsuccessfullyemployedinthetreatmentofPD. stage, ithasleftalastinglegacyasthepioneerdopamine changes including:reducedventromedialhypothalamic once daily 1 SHR ratdemonstrate that injection of bromocriptine ( nucleus thataffectsympatheticoutflowtotheperiphery and through connections to the suprachiasmatic action attheventromedialnucleusofhypothalamus may beduetoitsloweringofsympatheticdrivean by39%( angina andrevascularizationsurgery hospitalization for congestive heart failure, unstable cardiovascular endpointofmyocardialinfarction, stroke, safety studyofsome~3000patientstolowerthecomposite levels. It was shown in a randomized, double-blind, 1-year fasting andpostmealplasmafreefattyacidtriglyceride hyperglycemia. Circadian-timed Cycloset alsoreduces be mainly(thoughnotsolely)viaactiononpostprandial basal/bolus insulin( and by1.1–1.8asadd-ontherapytometforminplus 0.5–0.9 asadd-ontherapytooralanti-diabetesagents bromocriptine Dopamine agonists: 44 h ofwakinganddesignedtobemorerapidlyabsorbed ). Studiesperformedinexperimentalmodelofthe Bromocriptine isapprovedintheUSAfor mg/day, it lowers HbA1c in T2DM subjects by hour before lights off leads to remarkable Parkinson’s diseaseandendocrine-related 15 h 1–3 h 72% 28% Non-micronized Parlodel diseases 44 ). ThisCycloseteffectappearsto Downloaded fromBioscientifica.com at09/28/202109:59:47PM 43 ). Itappearstohavegreat 179 www.eje-online.org :2 al 1 Table 42 ). In2009, ). Itsrole 45 ). This R73 via freeaccess European Journal of Endocrinology www.eje-online.org References the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagency in Funding this study. the authorshaveanyinterestsindopamineagonistsattime of developing MK-0677(ibutamoren)asghrelinreceptoragonist.None of the founderandChiefScientificOfficer ofAmmonettPharmawhichis Dr BesserhasnodeclarationsofinterestorfundersandThorneris Declaration ofinterest important therapeuticimplications. the journeycontinuestohaveinterestingandpotentially years later, therearestillmanyquestionsthatremain,but metabolic syndrome and its associated morbidity. Fifty bromocriptine maypreventthemfromdeveloping frequently exposedtofooddeprivation.Perhaps,timed since humansfortunatelyinthemodernworldareless syndrome and type 2 diabetes may be a maladaptation glucose for the brain. Thus, it is suggested that metabolic non-CNS tissuetotherebysparetheproducedhepatic hepatic lipogenesistogeneratelipidasafuelsource for is availableinthe wild and yet increase insulin-mediated insulin resistant to generate glucose when little to none resistant animalsevolvedtheabilitytobecomehepatic by theclock pacemaker. Seasonally obese, insulin- occurs. Thehepaticmetabolismappearstoberegulated them for their needs when famineor short supply of food mass, insulinresistanceinseasonalvertebratestoprepare pioneered thiswork,drawtheanalogyofchangeinfat control SHR rats ( gluconeogenesis andfreefattyacidoxidationversus of themastertranscriptionalactivatorslipogenesis, pathwayproteinsand levels ofseveralproinflammatory bromocriptine treatmentsignificantlyreducedhepatic adiponectin significantly relativetoSHRcontrols.Finally, and norepinephrineincreasedthoseofplasma also reducedplasmalevelsofC-reactiveprotein,leptin relative tovehicle-treatedSHRcontrols.Suchtreatment body fat,plasmainsulinandglucoselevelsHOMA-IR and systolic and diastolic blood pressures, retroperitoneal norepinephrine andserotoninlevelstothenormalrange 2 1 Review Shelesnyak MC. Progesteronereversal ofergotoxineinduced Fluckiger E &Wagner HR. influenceon 2-Br-alpha-ergokryptin: Endocrinologica suppression ofearly–pre-implantation –pregnancy. (https://doi.org/10.1007/BF02147804) fertility andlactationintherat. 1956 46 23 ). Cincotta and colleagues, who have 151–157. Experientia others G MichaelBesserand 1968 24 1130–1131. Acta

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European Journal of Endocrinology

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