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    The Effects of Pharmacologically Induced Hypogonadism

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    Mariana Creciun

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    EE The Effects of Pharmacologically Induced Hypogonadism on Mood in Healthy Men Peter J. Schmidt, MD; Kate L. Berlin, BA; Merry A. Danaceau, RN, MSNCS; Amy Neeren, BA; Nazli A. Hag, MA; Catherine A. Roca, MD; David R. Rubinow, MD Background: The effects of declining androgen secre- jon on mood regulation and the potential psychotropic elficacy of androgen replacement in men are largely tn- determined. Objective: To examine the effects on mood of the acute suppression of testosterone secretion, Design: A double-blind, placcbo-controlled, crossover GelF-as-own-control) study Setting: Anambulatory cate clinicina research hospital Participants: Thirty-one healthy adult men with no his- tory of psychiatric illness or substance or anabolic ste- roid abuse Interventions: Men received depot leuprolide acetate (Lupron, 7-5 mg intramuscularly) every + weeks for 3 months. Afler the first month of Lupron alone, all men received (in addition to Lupron) testosterone enanthate (200 mg intramuscular) or placebo (sesame oil as color- matched vehicle) every 2 weeks for 1 month each in a crossover design. The order of administration of testos- terone and placebo was randomly assigned and counter- balanced. Main Outcome Measures: Mood and behavior rat- ing scores (self-report and rater administered), Results: With the exceptions of hot flushes, libido, and the feeling of being emotionally charged, none of the symptoms measured showed a significant difference across eugonadal, Lupron plus placebo, and Lupron plus tes- tosterone conditions, Despite the absence of uniform effect of Lupron plus placebo on mood, 3 men experi- enced clinically relevant mood symptoms during this in- duced hypogonadal condition, High baseline levels of sexual fanctioning predicted the greatest decline in sexual function during Lupron plus placebo. Conclusions: These data, the first to describe the ef- {ects on mood of induced hypogonadism in healthy young, men, suggest that short-term hypogonadism is sulfi- cient to precipitate depressive symptoms in only a small minority of younger men. The predictors ofthis suscep- bility remain to be determined. Arch Gen Psychiatry. 2004;61-997-1004 HE AGE-RELATED DECLINE IN circulating androgen lev- els progresses to hypozo- nadism in a substantial number of men'? and may studies. Clearly, the mood effects of an- drogens are not uniformly observed in ‘men, and the reported antidepressant re- sponse may rellect the reversal by testos- terone of age- of illness-related sarcope- Author Affiliations: Behavioral Endocrinology Branch, National Institute of Mental Healt, National Institutes of Health (rs Schmidt, Roca, and Rubinow and Mss Berlin, NNeeren, and Hag), and the Department of Nussing, National Institutes of Health Clinical Center (Ms Danaceau), Bethesda, Ma. (aePRUTED) ARCH GEN PCHIATRVOL GT, OCT Toe have a negative effect on bone metabo- lism, muscle mass, and, possibly, mood and behavior.» Androgens have been im- plicated in the regulation of mood by sev- eral types of evidence. First, in con- trolled clinical studies, supraphystologic doses of androgens (eg, anabolic- androgenic steroids) induce prominent ‘mood changes (hypomania, irritability in approximately 5% of eugonadal men.** Second, in placebo-controlled clinical tials, physiologic doses of testosterone produce antidepressant-like effects in hy- pogonadal men in some" but not all nia (reductions in muscle mass) and fatigue" instead of a direct action of an- drogen on mood. Moreover, several con- textual factors could influence and, hence, complicate the interpretation of the ins ences drawn about the relationship be: ‘oven androgens and mood, including im- pact of concomitant medical conditions histories of psychiatric illness, substance abuse, and prior exposure to anabolic- androgenic steroids °° No study has ex- amined the effects on mood of the acute withdrawal of testosterone in eugonadal healthy young men, (©2004 American Medical Association. AI rights reserved, The purpose of this study was to address existing con- founds by examining the effects on mood of the acute suppression of testosterone secretion with pharmaco- logically induced hypogonadism in young, healthy adult men with no history of psychiatric illness o substance or anabolic-androgenic steroid abuse. Es} SUBJECT SELECTION Subjects were menaged 18 1o 45 yeas erated through aver temnents and releeed rom the National Tnstutes of Health (StH) Nowal Volunteer Otee All were mediation lee, had sigan medial line carey orm the as 2 yet) td had nora aboratory sess Spell, complets ood Cal counts blood chem. thyrod Tancion teste (you Stimulating hormone and fe hyronin) and prostatespeciic antigen levels were within normal limite: Addionally, pasa teal estowerone level xd rom 335 to 992 mpl. 2 54 nmol) (oormal range 300-1200 ng. [104-416 nal 1a plasma prolactin vee were win nore its (1-16 npn nal ut sujet whose plasma prolactin 29g ouepeat testing, The sisene ef caren or pst pjehnne tswesconfied byastuctred poetic degnstic ie Toe and daly gonpbcele ange Senenured intros wee pevlornedby lof totus(]S-MAD:NAG orc AR) Sab Res were exchde om tts sind i they hada pastor present Peychitc Uns or evidence of prsitat (235 days) eli Ely significant mood and behave ympiomsof moderates ‘erty om the dal symptom rating form ee “Outcome Mes Stes) during ter scrceing phase The protocol was viewed tnd approve bythe Nation Instate of Mena leah int tural rscarch board, and oral and writen informed consents tere obianed fom ali subjects All subjects were pid or their parcpaton nth protocal according tothe guidlines of the il Normal Volunteer lice PROCEDURE This was a double-blind assessment ofthe effects ofthe acute induction of hypogonadism and subsequent replacement ina Crossover design with testosterone and placebo. Alera 2amonth screening phase, men reclved 7.5 mg of intramuscular CM) depot leuprolide acetate (Lupron; TAP Pharmaceuticals, Chi cago, II) every 4 weeks for 3 months, Lupron alone was al tmincered forthe fist 4 weeks, subject then received, nal dition to Lupron, 200 mg of M testosterone enanthat (Bristol ‘Myers Squib, New York NY) or 13 of IM placeo (sesame oil as color matched vehicle) every 2 weeks for | month Ge, twice) and hen cross-over tothe other replacement, The oF der of replacement was randomly assigned and counterbal ‘nce. Men were scent the National institute of Mental Heath cline every 2 weeks throughout the study Blood samples were chained and symptom sleratings were completed at cach cline vision a biweekly bass throughout the study. Both subjects and raters were blinded to the onder of replacement. all sub- jects were taking Lupron throughout the study, and thersfore their endogenots testosterone secretion was suppressed, ob- iatng the need for collecting samples at uniform ie point. Blood samples were taken solely to confirmbormone levels dur- ing each ef the pharmacologcally induced hormone cond tions, Each individual came tote clini at approximately the same time during the study ut the time of day for vise ar ied across Individuals. Blood samples were centrifuged, all Guoted, and stored a 70°C unl ime of assy (aepRU\TED) ARCH GEN PCHIATRVVOL GT, OCT Toy OUTCOME MEASURES To asses the severity of mood symploms, the following symp- tom rating forms were completed a baseline and during each hormonal condition: (1) vista analogue sale" completed righ forall symptoms scores range fom (symptoms pres- tat inthe extreme) to 100 (symptoms not present) and reflec the subjects symptoms at the time the ratings were com pleted; and (2) the Dally Rating Form, 3 point Likert-type ‘calemodifi io incide the symptoms messured in thisstady also completed nightly, to represent a composite rating forthe Previous 12 hours; scores range from 1 (eymploms tot pre- end to 6 Geymploms present i the extreme). The Dally Rat- ing Form symptoms consist of the fellowing: avoidance of so- Cia activi, Loe of enjoyment or intrest, mpaed function ‘work or home; irtabliyor anger; impaired concentration or dutraciblty, mood swings: Teling depressed ad ow, or ble; feling ansious of nervous; decreased cating, tnereased cating, more seep. nape or lying in bed low energy, lonel- tess feeling rejected, feeling physically restless or alate, feeling powerful, emotionally charged. ot pumped up in creased sexual intrest decrease seul nterest disturbed sleep, drinking alcohol or using nonpresrbed drugs: impulse to hurt self impulse to hurt someone else; acting on impulse to hurt. omeone: daytime hot fushes; and nighttime hot ses, Thie- teen symptoms recorded bythe visual anlogue scale con- Sted ef tne following raply changing mood, increased ap Petite ravings labeling best evertwort ever. impulse {o hurt others, low sel-esteem, impulse to hurt sl, sadness, Instability, Low energy, functional impairment, ket. ex: tteme physical dlscomfor, and eolation and social avoidance Four men did not complet the Dally Rating Form ratings and 2 men didnot complete the visual analogue sale ratings The following standardized rating scales also were competed dur- ing each clint vst: the Beck Depression Inventory (BDD), 3 measure of depression severity" and the Spelbergr Sate- Trait Anxiety Inventory, 2 measure of anxiety severity.” Because measures of howlityhavebeen correlated with es- tosteronelevelsin a variety of stds abet not unflormly) ‘weatempiediodetemine whether induced hypogonadism would beassoisted wiharcducton nsellratingsof aggression. Asub- sample of 2mencompleted rating forms that assessed changes inthesubjece experiences of aggression, anger and impulive- ‘ese as follows: (0) Buse Durkee Hostility Inventory (a Scalemeasuringthesubscales of asall, direct hott ob jectismot direct target of hoslity), tbl, verbal hosiiy, ful spicon, esentment and negativity) (2) Ange, Ie Faby and Assault Questionnaire” (242-iem scale asese- igvaiaheesuchasirntabiliy verbal aca, direct sell, direct assault, and anger); and (3) Barratt mypulsivencss Seale wersion 7B (a e-em scale measuringrisk aking, interpersonal behavior, motor Behavior self-ascessment and sensory stimi- Inion)"> (all rating form were modified reflec acubjec's experience during the 2 weeks prior to completing he sales) HORMONAL ASSAYS Blood levels of testosterone, free testosterone, estradiol, and hhydrotestosterone were measured by radioimmunoassay, as de- scribed previously" (Quest Diagnostics, Baltimore, Mad, and Covance Laboratories, Vienna, Va) STATISTICAL ANALYSIS ‘The T-day averages of the daily symptom scores were caleu- lated during the fourth week of the 3 experimental condi- tions: baseline, Lupron pls testosterone, an Lupron pls pla (©2004 American Medical Association. AI rights reserved, ‘Downloaded From: https:/jamanetwork.com/ on 12/13/2020 Table 1. Hormone Levels During th or Testosterone in 31 Men seline Period and During the Administration of Lupron Pus Placebo ase ‘apron Lupron Pus "ANOVA Fi Hormone Normal Range Means Placebo, Moan s SO Testosterone, Means sD (PVatie) Testosterone, ai 300-1200 «2 1S BOs ZL a0 = 4612 197 (<0) Free testosterone, pl. 11 00877 pester a7 24h 1397 (<0) Dindratststarone gl 2595 2sto Ob suet 4502281 381 (<0) Esta, pi. 1050 aad azetet 2532135 37400) Abbrvition: ANOVA. analysis of variance with repeated measure. Sleamversion act To cont tsostarono to nanomoies ey, multiply by (0847.1 convert asta picomoles per tr multiply by 387 “P= Ot ferhypogoraalshassine sing post-hoc Bnfron tests (2 ale), 42 01 ferhypegoraalvs testosterone repaced using post-hoc Boron tests 2 ale), 43? < 01 forbaselnew eststrne replaced using post-hoc Befron tests (2a), eho, Cross-sectional rating scores (forthe BDL, Spielbergr State ced with changes in testosterone levels across these condi- Trait Amity Inventory, se Durkse Host Inventory Anger, tons This, forthowe symptoms tht caged sgn eros Testability, and Awash Questionnate, and Baeat Impulse: hormone cantons Ge, BDI scores, ho she, sex ner nes Sal version 7) were taken from the lst week ofeach stand feeling emotionally charged), correlations Were per phase The averaged dallyand ingle cons-sectional symptom formed with the following manors of testosterone: (1) the Scores were compared byanaljiselvaranecwithrepeatedines- changein he average testosterone level recorded irom he tee sores (ANOVA-R) (Syst SPSS Ine. Chicago, ID, with hor. tostrone-repaced to the hypogonadal conditions snd (2) the ‘onal condition (bstine vs apron ps estonterone vs ik. maximum change (cll by dentin the highest level pron pis placho) asthe within-subjects variable. Analyses of of testosterone obained and subtracting t fom the lowest fariance were reperformed sing subject age a6 covariate. plasma testosterone level during the hypogonadal tt) Symptmting dns during th est month apron ons) errs i ican eee reana acme Ide ere forte) ant as cease ot ES tpn ccusinel cence fake esbeoten ect Infuse tenon corer BDl WDLseare cla Sy ce Sept onan) sco hon on smth hc ehereuat at Timmer eck eBineddungthe st 2 weeksafThity-one mem ranged In age fom 25 to 46 yeaa cach alt uck condition (estotcrne graces) wceaer: Geeaaab aoaaae tein heintet ncn ecw ee aged and compared by ANOVA-R with hormone condition as pron plus testosterone first, and 17 received Lupron plus the within-subjects variable lacebo first after 4 weeks of treatment with Lupron alone. Seminal earicrstudies®" demonstrated thatthe behav- Placebo first after 4 weeks of ta Lpronal toral response to hypogonadism and testosterone replacement inanimal could be predicted by pretreatment levels of androgen- HORMONE MEASURES related behavior. To determine if these observations could be extended to humans, we assigned subjects to I of 2 categories defined by theirbaseline symptom scores on 2 behavioral symp- toms, ie, sexual interest and feling emotionally charged, iden- tied by ANOVA as changing significantly across the 3 hor- onal conditions. The 2 subject groups comprised the 10 SUBJECT CHARACTERISTICS Lupron plus placebo was associated with significantly lower plasma levels of testosterone. free testosterone, di- hydrotestosterone, and estradiol than either the eugo- nadal (baseline) oF Lupron plus testosterone conditions Subjects wit he highest high group and lowest low group) Fable 1), Plasma levels of both total testosterone and baseline scores onthe 2 selected symptoms, Their scores for fee testosterone were significantly higher during testos- these ?sympoms were analyzed By ANOVA'R wih base. terone replacement than during baseline. No significant linesymptomscor Cow vahighasthebetween-anbject vare differences in plasma levels of cikydrotestosterone ot ex- ablcand hormonal conditions the win subjects arable. radiol were observed between baseline and Lupron plus Fost hoe Bonferon tests were performed Wihinand be. testosterone tween groups when indicated by sigaificant ANOVAS. Two- tailed ests were performed to compare baseline plasma lev elsof testosterone and estradiol between high and low baseline SHPO OP : fo examine potential order effects on significant symptom With the exception of hot flushes (both daytime and night- measures, we peated the ANOVARwithorderofreciving es jm), libido, and feling emotionally charged, there were tosterone asa between gzoup factor. Additionally, t0 avoid 89y significant differences between the Lupron pls pla- potential conound of hc cscoverdesignon kc observed ch" ences betwen the Lp fesofLuponplasplccho ye reamlycdthedataby ANOVA <&bo Condition anther dhe beeline or the Lupron plus including baseline and only the fist hormone treatent that each subject ceived (ee, peeuloparallel design), cluding sadness, anxiety, irritability, mood lability, an- Finally, Pearson correlation coelicients were performed to __‘hedonia, and decreased energy (Rabble 2). Hot flush (day- examine whether changes in symptom scores between the tes-_ time and nighttime) severity significantly increased and tosterone-replaced and hypogonadal conditions were associ- both sexual interest and feeling emotionally charged sig- SYMPTOM RATINGS (agen TED) ARGH GEN PNCHIATRVVOL GI, OCT Toy WAW.ARCTGENDSVGHIATRCOM (©2004 American Medical Association. AI rights reserved, jamanetvrork.com/ on 12/13/2020 Table 2. Symplom Ratings During the of Lupron Plus Placebo of Testosterone in 34 Men seine Period and During the Administration Lupron pes Tasetrne, ANOUK. cutcomewessre symptom Moan 80 Paco, ean » 80M eve) Bek Depeson eto 1m 05.12 2as324 «08a 734,00 Spisetpr Strat Ant Inetry NA eed0 281208 wisie2 —216(N5) Only Rating Form Sains 12204 13203 13205 O3tiNs) ‘nay taeod ia0a 13207 0th) aby 12202 13208 vais 1a01n9) Mood tay 12203, 13206 i224 s0iNs) detona 12403 12s04 valor 195(N5) ecenedsoualineest 1202 DatSi§ 13007 © 212(<000 Inve seaalinrest 17208 i2e03§ ©1508 122(<0) Wahine at ister 10200 ‘estos 14503123100) Daytma ot ushes 1200 ieee 14502 1420/09 Erotiraly charged 15208 i2eoa§ 1s 445 (05) Decree nergy 15205 isso jes0o Zz) biperaraia i208 14s08 1320@ o76iNs) Dated ep 13205, 15207 valor 106(N5) Decrene xg 1208 i402 zane azn) ines xing 13005, 1209 1as0s —158(hs) Physical ptten 1307 12208 ‘320g 88h) Inge tht al teat 19201 tora —o46iNs) Vu nog zal Mood sity 12.120 748108 radi 0158) Socal avoanca Sais? etait fat otis) Destased ork productly 615167 642187 G12 18D—_OTSINS) Ipueetohutaters 764156 © SORa 10 © 9032125145 ) Seat mesmo © 7132200 tab —_OBTINS) ‘Abbreviation: ANOUA-R, aaj of varince vith apeated measres; A not ppeabl ae NS, ot sina. “ANOVAs for Beck Dpresson InventeySpeberger Start Act ventory, seal f= 256, "26 or Day ting Form, d= 2.52, = 27: and rvs analog 42'= Of for Lupron pls placebo vs tase using ost hs Bonfranests (2 aed), >< 05 or Ligron pls placebo vs Lupron plus tastostrona sing postho orton rats (2 tale). 8 < 01 for Lupron pls placebo vs Lupron plus tastostron using post hos Borferan ats 2 tale). nificantly decreased during Lupron plus placcho com pared with both baseline and Lupron plus testosterone. There were no symptom differences between baseline and Lupron plus testosterone. Repeated ANOVA with age as a covariate resulted in an identical pattern of effects Beck Depression Inventory but no Spielberger State- Trail Anxiety lnventory scores sigaficanly increased dur- sng Lupron pls placebo compared with baseline and Lat pron plis testosterone. The increase in BDI score during Lupron plus placebo (meanaSD, 2323.2) was statisti cally but not clinically significant and reflected the ef fects of 3 men who scored 7 of higher on the BDI dusing Lupton plus placebo compared with none dating La- pron plus testosterone replacement (Fisher exact test, P not significant). One man met DSM-IV" criteria fora max jor depressive episode during Lupron plus placcho, and his BDI scores were 0a baseline, 14 during Lupron plus placebo, and | during Lupron plus testosterone. We ob- Served significant ellects of order of hormone adminis: tration and a trend for a significant interaction between order of hormone administration and hormone condi- ion on the scores ofthe BDI (ANOVA-R: effects of oF- der, Fyyy=7.0, POF; tnteraction, Fase=25, P09). A similar pattern was observed for the symptom of de- exeased sexual interest (ANOVA-R: effects of order, 19.5, P<.0O1: teraction, Fs5y=4.1, P<.05).Men receiving Lupron plus placebo first but not those receiv= (aepRU\TED) ARCH GEN PCHIATRVVOL GT, OCT Toe {ng Lupron plus « cant increase in BDI scores (and a decrease in sexual in- terest) during Lupron plus placebo compared with baseline conditions (0,,=3-+ and t4y=3.7, respectively P=), Total scores on the Buss-Durkee Hostility Inventory Anger, livitability, and Assault Questionnaite, and Bar” att Impulsiveness Scale version 7B did not change across hormonal conditions; however, several individual sub- scale seores changed significantly from baseline with study participation. Buss-Durkee Hostility Inventory assault scores decreased from baseline during both Lupron plus placebo and Lupron plus testosterone (with significant differences between baseline and Lupron plus placebo). A similar pattern of change was observed for the indi- vidual subscales of risk taking, motor behavior, and sen- sory stimulation on the Barratt lmpulsiveness Scale ve sion 7B rable 3). There was no significant interaction between order of hormone administration and hor- mone condition on the scores of either the Buss-Durkee Hostility Inventory assault or the Barratt Impulsiveness Seale version 7B subscales, ‘Men were assigned to high (n=10) and low (n=10) symptom groups for the baseline symptoms of sexual in- terest and feeling emotionally charged. There were sig- nificant group X hormone condition interactions for both sexual interest and feeling emotionally charged (ANOVA-R: osterone first experienced a signili- (©2004 American Medical Association. AI rights reserved, Table 3. Symptom Ratings During the of Lupron Plus Placebo of Testosterone in 20 Men eine Period and During the Administration Tesloserons, ANOVA Fe outcome Measure Symptom ean = $0 ‘Mean 280 (aus) ee Durkee Host ventory ssa a7a20 wala 3a=05) Indirect hoety a5at8 33420 4 ns) Ita 32.23 32426 105 (Ns) Vera 74323 60.25 1.0(Ns) Guat 2osta 23420 108s) Suspicion ogs13 ogatt 165 (Ns) Resentment o7s09 o7ata 14 is) Ngati 15212 15416 03 (Ns) Ange ety and Assaut Questionaire ——_ritabity se.30 Taso 1065 (Ns) Verbal ars ass55 oesas 12(N8) Indrac aeaut 21s38 30230 12 (Ns) Dict seat a0sa2 25435 103 (Ns) Anger 22532 25431 105 (Ns) Barat impulsiveness Seale version 78 Fisk aking eases 8755p 85,001) Inarpersonal bebavor = 3.1229 araao 0s) oar batavior 145266 1194545 33 (05) Sataceesment 167288 = 140201 ‘Sostod © 10(NS) Sensory stmulaton 65235 Ba20" 58428 a7(<.05) Aibrevition: ANOVA, ans of varie “P05 or Lupron pls placebo vs taal $B 9 for Lupron plas placebo stalin $< 01 torLugron pls testosterone vs a sing post hos Bo vith raped measures aed NS, ot sgneat rn sal usin pst ho Bntaran ests 2 tale). ng post hee Bonferroni tests 2 ale), P< 05 or Ligrn pls testosterone vs basal using post hoe Boferran tests (2 tal), Fiig=5.9, P<.OL, and F, =11.6, P<.001, respectively). For both symptoms, scores for the high symptom group were significantly higher than those for the low symptom group during baseline (by definition) and Lupron plus tes- tosterone but not during Lupron plus placebo (baseline: 6258, P01, and t4=5.5, P

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