Antunes-Rodrigues, J.

Foss,  M. C.

Iazigi, N.

Lima Filho, E. C.

Moreira, A. C.

Verissimo, J. M. T.

English

Cadernos Espinosanos (E-Journal)

Rev. Inst. Med. top. São Paulo24(3) :148-154, ntaío-jtutln, 1982LUTE¡NIZING HORMONEa. c. MORETRA (1), J. ANTUNES.RODRTGUES (2), E. C. LIMA FrLHO (3), M. C. FOSS (t),N. IAzIcI (1) antt J. M. T. VERISSIMO (1ìLuteinizing hormone (LH) secretion was investigated. in men with chronicchagas' disease as 'well as in control subjects, under basal (pulsatile pattem) andstimulating conditions (LH-RH and clomiphene citrate tests). The chagasic groupexhibited a greater dispersion of i,ntegral LH lovels under basal conditions that thecontrol. The frequency of secretory spikes and the meân concentration of tes-tosterone measured in 12 blood samples drawn over a B-hour period, were normal.No functional disorder of pituitary LH secretion following acute and continuousLH-RH infusions was detected. However, in the chagasic group the values forindividual LH release under clomiphene citrate treatment were abnormally scatter-ed. These results suggest the existence of a hypothalamic ctysfunction in chagas'disease.SECRETION IN MEN WITH CHRON¡C CHAGAS'DISEASE ('')SUMMARYUDC 593.161.136L6.937 .3A loss of efficiency of the mechanisms con-cerned with the homeostasis of circulating thy-roid hormone seems to occur in patients withchronic Chagasdiseass 12. KIMACHI et al. 10concluded that there seems to be somè abnor-mality in the regulation of the pituitary-adre-nal axis. However, no functional disorder,s ofthe thyroid gland or of the adrenal cortex coulclbe demonstrated. They suggested. that the con-trol mechanisms for secretion of thyroid..stimu-lating hormone (TSH) and adrenocorticotropicIromone (ACTH) were disturbed in Chagas,disease, This could be a result of the neuronallesions characteristic of the disease lt, which isparticularly evident in the visceral autonomicinnervartion, and also demonstrable upon postmortem in the anterior region of the hypotha-lamus of patients with chronic Chagas' disease +.INTRODUCTIONThe present study was designed to exploresome aspecfs of the regulation of luteinizinghormone (LH) secretion in patients with chro-nic Chagas'disease.MATERIAL AND METHODSSubjectsThe subjects were l0 healthy male volUn-teers and 11 male patients with chronic Chagas'disease aged 20 to 50 years. T'he controls agerange matched to the chagasic patients. Thediagnosis of Chagas' disease was based on apositive Machado-Guerreiro complement fixa-tion reactions and fluorescent antibody test6in patients from endemic areas with treatedmegaesophagus and megacolon or chronic cha-ga,sic cardiopathy without heart failure 11. AIl(*) (1) Departments of Clinicat Medicine(2) Physiology(3) MathematicsFaculty of Medicine, Rit¡eiráo preto, Sáo paulo, Bì.asilSupported by FINEP (Financiadora de Estudos e projetos)B/39 /1e /349 /oC/00148MOR'EIRA' A. c.; ANTUNES-RoDRIGUES, J.; LIMA FILHO, E. c.; Foss, M. c.; IAzIcI, N. & vERÍssIMo, J. M. T..._ Luteinizing hormone secretion in men with chronic chagas'disease. Rev. Inst. Med. lrop. são paulo 24tr4s-t54, lgg2.the subjects exhibited no clinical evidence ofendocrine disease or undernutrition. They werenot receiving medical treatment at the timeof the study.ProceduresAll tests were performed between B:30 and9:00 a.m. without fasting. In the studies in-volving frequent blood sampling, a heparinized,scalp vein needle was inserted into an antecu-bital vein. Small amounts of heparinized salinewere injected after each blood collection. Bloodsamples (3-4 ml) were kept in heparinized. glasstubes on ice. The plasma was separated bycentrifugation and stored at .20"C. Three expe-riments were carried out on the subjects ondifferent days.1) Determination of the individual pulsa-tile pattern of basal LH relea,se. Blood sampleswere drawn every 15 minutes over a 3-hour pe.riod for LH and testosterone measurements.2) Determination of the LH responses toLH releasing hormone (LH-RH). Synthetic LH_IìH (Escola Paulista de Medicina - São paulo)was injected as in i.v. bolus (200 pg) and blooclwa,s sampled a¿ -5, 0, b, 15, 80, 45, 6û and 120min from the time of injection. On a subsequentday, LH-RH was administered through a Har-vard constant - infusion pump at a rate of 0.2pg/min for 4 hours and blood was collected at-15, 0, 15, 30, 45, 60, 90, 120, 150, 180, 210 anC240 minutes from the start of the infusion.3) Determination of LH release afterclomiphene citrate. Clomid.-Merrel, B mg,zkg,zdaybut not more than 200 rrrg/c.;ay was administer-ed orally in two doses for B days. Blood wascollected on days 0, I,4,6 and B.Hormone AssaysPlasma LH was determined. in duplica:eusing the double antibody radioimmunoas,saymethod described by ODELL et al. rs. Reagentssupplied by the National pituitary Agency, USA(anti-LH batch No. 2 antisera and LER-960 HLHfor radioiodination) and produced in our labo-ratory (sheep anti-rabbit gamma globulin) wereutilized. The standard preparation (CALSTAN-II) was supplied by Calbiochem and expressedin mlU/ml using the Second International Re-ference Preparation for Human Menopausal Go-nadotropins (HMG-IRP2). The sensitivity of themethod was 0.50 mlU/tube. The within-assaycoefficient of variation was 6.BVo at 50.0%binding on the standard curve. At this level,between-assay variability was L4.0Vo.Plasma testosterone was measured in du-plicate by the radioimmunoassây method rusing commercial kits supplied by Trilab, SãclPaulo. The sensitivity of the assay was 25 pg/tube. The within-assay coefficient of variationwas Il.0%. Between-assay variability at 50.0%binding was 1l .0o/o.All samples obtained for each patient foreach experiment were analyzed in the sameassay to avoid interassay variability. The datawere analyzed according to the ratio SD.zchâ,-gâsic/SD.2 control, for the ,significance level åt5.0Eo 16. In the figures we also utilized. the ran-ge, the 10th (Pr') and gOth (Pno) percentile.Quantitative parameters of LH pulsesAn LH secretory episode (pulse) was de-fined as a series of values consisting of twoor more constant or decreasing concentrationsfollowed by two or more higher values 14. Theincrement from nadir to peak wâs equal to orgreater than 1.0 mlu/ml (3 times the coefficientof varÍation of LH assa.y at the 5.0 mlU,zml le-vel). The quantitative parameters determinedwere the mean concentration of LH from 12blood samples drawn over a 3-hour period, thenumber of pulses in 3 h and initiation (iowset-point) ând cessation (high set-point) of LHsecretory activity. The parameters were deter-mined a,s described by BOYAR et al.3 andSANTEN & BARDIN 18.RESULTSPattern of B¿sal LH ReleaseThe results are shown in Table I and Fig.1. The mean and median LH values for con-trols and chagasic patients were similar.However, in the chagasic group the individualdata are abnormally scattered, above as wellas below the limits of the control interval. Themen with Chagas' disease exhibited a signifi-cantly greater (P < 0.05) dispersion of indi-vidual mean concentration of LH in relationto the control timits. A wider range of variationthan that of the control group is al'so apparentin the chagasic subjects when the values for149TABLE Ipattern of basal LH secretion and testosterone concentration during a 3-hour study period in control and chagasic menControlsubjectsLow5ecretorY set-poi ntspikes/3h LH mlU/mìHighset-poi nt Mean*/3hLH mlU/mì LH mlU/mìHean /3hTe s t os te ronengl 1 00m IChagas Ì c Secretorysubjects spikesT3hLow Highset-point set-pointLH mlU/ml LH mlU/mìHean/3 hHean*/3h TestosteroneLH ml U/ml ngl100mì3\oB9l0|4ed ianHean+S D .tSD. -Þ -Þ'10 '90o.ua110.1qq5.7l¡qÁob. tLa6.0o,)+r,yJ.bn,I-J.73À6789l01lHedianMean+S D .7SD. -^^2)u. cnagas r c))u. confro I7.01Q1.61t).o2.12.1?13 .81t .94.4**qqoq11.0r0.82.78.8Rqr0.04.013.26.012.23-4r to2.41 2.32 3.85'01 3.01 3.11 4.32 2.71 3.11.4.0.5 3.2!0.90.25 0.811 -2 2.3-4.34.0+1.4 298.34.7+ì.8 iiz.B6 .7!2.0 234 .83.710.7 236.14.2!0.5 396.24.3+1 .2 639.63.7!1 .3 1\4.35.0+0 . B 57\.05.2+0 .63 .810 .7 281 . 1\.2 798.3\.5+o .9 j48.5+t62.90.81 26536:\3.7-5.2 234.8-574.o;1I11211| .3+0.1r0.r60 .646.8+2.03.310.7 392.56 ,\+2.0 406.03 .7!o .\ i 38. o3.6!2.5 571.02.8+0.6 291 .68 . 510 .9 \67 .37.0+1 .1 957 .55.7+1 .8 63\.7? ?¿1 '7.4!2.3 278.35 .7 406 .05.3+2.0 \59 .1+2\0 .54.0 57840 .z4.9** 2.2Ktp¡ÈdçÞo!.ÞN'='m:,it9ÞáZXFIÉé@zHÈ.HÐ?Fõ'3. -'^EÉÞi.HôrÍpaìaoAA'úfgH.rrXN'^YVKpe'S)1?oÙDo^, II'=à_o;B* Hean + SD. (n = t4,) ** P < o.05MoR'EIRA, A. c.; ANTUNES-RoDRIGUES, J.; LIMA FrLHo, E. c.; Foss, M. c.; fAZfGl, N. & vERfssrMo, J. M. T..._ Luteinizing hormone secretion in men with chronic chagas'disease. Rev. Inst. Med. trop, são paulo 24:148-t54, lgg2.o3-hour mün LH lcvcls mlU¿tnlqõÞl-or rt-pohf)DÞD )oq, fl-,pbrrm LHõ(rl(rlLH Rele¿se during Clomiphene Ciúrate Admi.nistrationPlasma LH levels rose progressively duringadministration of clomiphene in both groups(Table II). The mean values reached in thechagasic group 'were not significantly differentfrom the corresponding controls. However, inthe chagasic patients the individual dâta areabnormally scattered, above as well as belowthe control range (Fig. 3), but only on day Bthe difference between the respective variancesis statistically significant (P < 0.05).DISCUSSIOT{The present study indicates that men withchronic Chagas' disease exhibit a peculiar ab-normality of the pattern of basal LH release.This dysfunction i.s apparent as a considerabledispersion of the individual mean concentra-tion of LH per 3 h a,s compared with the con-trol lÍmits. Since the individuarl mean LH plas-ma levels determined from multÍple samplesmight be a useful index of integral LH secre-tion r¡, we attempted to identify the site ofLH dysfunction in chagasic men.The individual mean concentration of tes-tosterone blood levels per 3 h were not ab-normally scattered in the chagasic men. The-se data suggest that these aþnormal but subtlechanges in plasma LH levels were not accom-panied by testicular testosterone secretion dys-function in Chagas' disease.In order to get a better understanding ofthe mechanism of altered LH secretion in thisdisease, the pituitary responses to LH-RHwere studied. The relea,se of LH in response toacute or continuous LH-RH stimuli were iden-tical both in chagasic and control groups andin agreement with earlier observations in nor-¡¡¡¿l ¡¡gn s,7,1e.These results indicate that the adenohypo-physeal LH secretion mechanisms were not pro-bably disturbed in Chagas' disease.However, when the effect of clomiphenecitrate on LH plasma levels was examined,the results showed that chagasic men had LHvariations with a wider scatter than those ofthe controls. Since this drug interferes withhypothalamic and adenohypophyseal feedbackmechanisms for testosterone 2,13,17 we believeHþh rct-point plosmo LH mtUttnlooìõc¡mlu/mlFig. 1 - Pattern of basal LH release in chagasic men.(A), 3-hour mean LH levels, (B), low, and (C) high set-points for initÍation and cessation of LH secretory activity.The horizontal lines on columns show the conttol 10th andgOth Þercentilethe low and high set-points are considered.However, the difference between the respecti-ves variances i,s significant (P ( 0.05) only forthe low set-points.The frequency of LH secretory spikes, therelation higþ/low set-point, the mean concen-tration of testosterone (from 12 blood sam-ples drawn over a 3-hour period) and the fre-quency of episodic testosterone spikes in thechagasic group fell within the control range.LH Responses to LH-RHIn the chagasic patÍents the biphasic pat-tern of LH secretion during the four-hour in-fusion of LH-RH was within the control range(Fig. 2). The responses to one-bolus intrave-nous LH-RH were also similar in both the cha-gasic and control groups.(¡MoREIR.{, A. c.; ANTUNES-R'oDRIGUES, J.; LIMA FILHo, E. c.; Foss, M. c.i r¡.zr1t, N. & vERÍssrMo, J. M. T.- Luteinizing hormone secretion in men with chronic Chagas'disease. Rev. Inst. Med. trop. São Paulo 24:148-154, 1992._ CHAGASIC--o CONTROL RANGEEf,?ôEl cqØ¿J10T,q.BLE IIPlasma LH levels during clomiphene citrate administration(3 mg/kg/day) to control and chagasic men-15 0 15 30 45 60 90 120 r50 r80 ?10 ?40ÏIME (MINUTES)Plasma LH mlu/mlControl(n - 9) 5.7!L.4 5.L!2.3 8.8!2.7 7L2!2.6 11.4!1.9Mean È SD.Chagasic(n : 11) 5.4!2.3 6.8!3.4 It.7!4.2 !3.41:4.1 14.4+6.6Mean i SD.Day of Test1468Fig. 2 - Plasma LH con-centrations ptior and du-ring 4-hour iv infusion ofsynthetic LH.RH (0.2þC/min) in ten chagasicpatients (^-A). The con-trol range obtained in tennormal subjects indicatedby 0-0SD.J chagasic 2.8SD.P control" P<0.05that the abnormal responses to clomiphene inthe chagasic subjects were determined. by aþy¡pothalamic dysfunction.These results suggest that men with chro-nic Chagas' disease exhibit an âIteration in in-tegral basal LH secretion determined by a de-152rangement in quantitative hypothalamic regu-latory mechanisms. The additional finding ofaltered low and high set-points but in the sa_me direction as that of the mean individ.ualLH basal secretion, is compa,tibte with this idea.It was also noted that alterations in fre-quency of LH secretory pulses could not.beseen in Chagas' disease. These findings arein agreement with the hypothesis that the cen-tral regulatory mechanism governing pituitarygonadotropin release is made up of a pulsa-tile and a quantitative component, independentof each efþg¡ 8,20.Our results are also in agreement withothers obtained for chronic Chagas, disease.These include the probably altered. secretion ofthe TSH 12 and ACTH 10. A common denomi-nator for all these dysfunctions seems to þethe decreased number of neurons in hypotha-lamic and extrahypothalamic structures inchronic Chagas' diseases4,1t. Although the rela-tionship þetween the subile hormonal altera-2.5 12.0"MOREIRA, .4. C.; .q,NTUNES.RODR.IGUES,- Luteinizing hormone secretion in mentions and the clinical manifestations was notevident, it is clear tha,t chronic Chagas' dis-J.; LIMA FILHO, E. C.; FOSS, M. Ç.i fAZfGI, N. & VERÍSSIMO, J. M. T.with chronic Chagas'disease. Rev. Inst. Meal. trop. São paulo Z4:t4B_lÐ4, t982.. CONTROLS¡ CHAGASICEfEeâse has a some form of neuroendocrine dys_function.l-t Ålß^vr4DAY OF TESTRESUMOSecteção do hormônio luteinizante no ht¡memcom rnoléstia de Chagas crônicaA secreçáo do hormônio luteinizante foi rea-lizada em pacientes do sexo masculino comcioença de Chagas crônica e indivíduos contro-les, sob condições basais (secreçáo basal pulsá-til) e de estímulo (testes do LH-RH e citratode clomifene). O grupo chagásico mostrou umamaior dispersáo dos níveis do LH integral emcondições basais que o,s apresentados pelo gru-po controle. A freqüência dos pulsos e a con-centração média de testosterona de 12 amostraspor um período de 3 horas, foram normais. Al-terações funcionais da secreção do LH hipofi-sário seguindo-se infusões aguda ou contínua deLH-RH não foram demonstradas. Entretanto, aliberação de LH durante o teste do citrato declomifene mostrou valores com maior disper-83¡a"f,Fig. 3 - Response of plas-ma LH to clomiphene citra-te (3 mg/kg/day) in controland chagasic men. Indivi.dual values are shown. Thehorizontal bar indicates thedulation of clomiphenetreatment.são, principalmente no 8.. dia no grupo chagá-sico em relação ao controle. Es,ses resultados,provavelmente, sugerem a existência de umadisfunção hipotalâmica na doença de Chagascrônica.ACKNOWLEDGEMENTSThe Authors are deeply grateful to MIYO-KO A. OWA and MAR,INA HOLLANDA for theirtechnical aid and to Professor HELIO LOU-RENÇO DE OLMIRA and Mrs. E. GREENEfor assistance with the manuscript. \.Ve alsothank the National Institute of Arthritis, Meta-bolism and Digestive Diseases, National pituita-ry Agency, USA, for supplying the materials forradioimmunoassay.REFERENCES1. ABRAHAM, G. E. - Radioimmunoassay of steroids inbiological materials. Acú¿ Endocr. Copenh. 188: ?-41,7974.f Ê2MOREIRA, A. C.; ÂNTUNES-RODRIGUES, J.; LIMA FILHÖ, E. C.; FOSS, M. C.; IAZIGI, N. & VERÍSSIMO, J. M. T.- Luteinizing hormone secretion in men with chronic Chagas'disease. Rev, Insú. Med. trop. 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M.; BURGER, H. c. & DUMpyS,R. - Serum LH and FSH response in four-hour infu-sions of luteinizing hormone-releasing hormone in nor-mal men, Sertoli cell only syndrome and Klinefelter,ssyndrome. J. Clin. Endocr. Metab. 4l: 8?6-896, 19?S.ELLICOT, A. R,.; BENOIT, R. J.; BORTH, R.; STRI-CKLER,, R,. C. & WOOLEVER,, C. A. - Effect of pen-tobarbital anaesthesia on luteinizing hormone Ievels inintact and ovariectomized eriles. Acta Endocr. Copenh.80: 32.41, 1975.FREITAS, J. P. L. - Reação de fixaçáo do comple-mento para o diagnóstico da moléstia de Chagas pelatécnica quantitativa: vantagens do método e sua apli-cação em Saúde Pública. Hospital (Rio) 4l: 256-262,7952.KIMACHI, T.; LOMONACO, D. A. & VERÍSSIMO, J.M. T. - Exploração funcional do eixo hipotálamo-ade-nohipófise-córtex adrenal na forma crônica da molés-tia de Chagas. Rev. Ass, Med. Brâsiì. ZOt 57-76, LgI4.KöBERLE, F. - Chagas' disease and Chagas' syn-drome: The pathology of Ametican trypanosomiasis.Adv. 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A. - Short and long-term effects of cl.omiphene citrate on the pituitary-testicular axis. J. Clin, Endocr. Metâb. 33: 970-9?9. l9?1.SANTEN, R,. J. & BARDIN, C. W. - Episodic Luteini-zing hormone secretion in man. J. Clin, Invest. SZ:2617,2668, 1973.WOLLENSEN, F.; SWERDLOFF, R,. S. & ODELL, ,w.D. - LH and FSH responses to luteinizing-releasinghormone in normal adult human males. Metabolism25: 845-863. 19?6.YEN, S. S. C.; REBAR,, R.; VANDENBERG. c. &JUDD, H. - Hypothalamic amenonhea and hypogo-nadotropinism: Responses to synthetic LRF. J. Clin.Endocr. Metab. 36: 811-816. 19?3.17.1Ð+Recebido para publicação em I312/L9BL.

Secreção do hormônio luteinizante no homem com moléstia de Chagas crônica

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Luteinizing hormone secretion in men with chronic chagas' disease

Luteinizing hormone secretion in men with chronic chagas' disease

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