PROSTAGLANDINS

POSSIBLE INTERACTIONOF PGF WITH BVPOTHALAMUS-PITUITARY2 alpha THYROIDAXIS IN MAN. G. Valenti,. G.P. Ceda, E. Tarditi, P. Chiodera, V. Coiro and U. Butturini. First Institute (Italvl

of Medical

A. Banchini,

Pathologv-University

P.P.

Vescovi,

of Parma

ABSTRACT on the hypothalamusThe.possible interactions of PGF studv. pituitarv-thvroid axis are the object’o?‘?&s infusion Firstlv a significant direct effect of PGF 2 alEha (mg2,5/270 mini on TSH,PRL,LH,FSH and GH pituitary ecretion was excluded. on PRL and TSH pituitarv Thereafter the possible PGF ina% P$ two cases PGF response to TRH was considered: 2 alpha was able to increase the TSH response. Finallv the Authors studied T resvonse to endogenous TSH rise induced bv TRH: if thev consider t ;te mean peak responses of T the infusion is perf armed. increase is significant onlv when PGF 2 alpha INTRODUCTION The object of this study is to examine the possible interactions with the hvpothalamus-pituitarv-thvroid axis in man. of PGF 15 ~~Dsdlawell known fact that medical literature has continued over the past few vears to add new experimental observations, in vitro and in vivo, which confirm the capacitv of some prostaglandins to modulate the function of some hvpothalamus-pituitarv systems. If we consider the recent observations of HEDGE(131 that confirm the previous results of PENG et al. (19) and of DeWIEDet ) seem to al. (9), some prostaglandins (PGE , PGFl lDha, PGF be able in the rat to release ACTB through a specif?ca&#thalamus stimulation. As for the gonadotropin incretorv system we find, beside numerous negative observations, also significant reports that emphasize a direct interaction of some prostaglandins. AMOSSet al. (3) showing that some inhibitors of prostaglandin biosvnthesis promote in vitro a decrease in LH response to the specific releasing, hvpotheticallv in fact showed the existence of some pituitary prostaglandin receutors. Some in vitro experiments of PRARRIS et al. (20) demonstrain pituitarv culture increased ted that the presence of PGF 2 alpha FEBRUARY

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FSH but not LH levels: thereafterin vivo, in ovariectomizedrats, HARMS (121 demonstratedthat PGE2 injectionin the third ventriclewas able to Dromote a huge increase of LH Dlasma levels and a slight increaseof FSH, while the effect was absent when PG injectionwas Derformedinto the oituitarv.Finallv SAT0 et al. (211 showed in vivo, in rats, the canacitvof PGE2 injected intravenouslv,to increaseFSH nlasma levels. ConsideringGH incretorvsvstem,medical literaturebecomes richer in observationswhich emDhasizedirect positive interactionof orostaglandins.SCHOFIELD (221, hiACLEODand LEHMEYER (16\, with in vitro exneriments,documentedan increase of GH svnthesisand release nromoted bv PGE , PGE and PGA . DROUIN and LABRIE (10) confirmedin vitro, for all h and 4 Drostagiandins , the caDacitv to release GH from nituitarvcells in culture but not when inhibitorsof brostaglandin svnthesiswere nresent in the mixture. Recentlv IT0 et al. (14) demonstratedin man that PGEl intravenousinfusionwas able to increase GH Dlasma levels. Even the nrolactin incretorvsvstem seems to be partiallvaffected bv some ru-ostaglandins. HARMS (12‘1,for example,demonstratedthat the injectionof PGEl directlv into the third ventricleof ovariectomized rats caused a huge increaseof Drolactin serum levels while the injectioninto the cituitarvwas without effect. SimilarlvOJEDA (17) in ovariectomizedrats confirmedthis response to PGEl with injection both into the third ventricleand the Dituitarvgland, even though in the latter the effect was decidedlv smaller; in anv case the resDonse is differentbecause oestrogentreatmentis able to inhibitPG effect in the former but not in the latter. Thereafterserum Drolactin in crease induced bv intravenousinfusion of PGE PGE and PGF 2 alnha in various dosages are describedin rats bv S.&O et2al. (21). There is scarcitv in literaturewhen we consider the nossible PG interactionswith TSH incretorvsvstem. The in vitro reports of VALE et al. (23) which on this subject document for PGEl the caDacitv in releasingTSH from the Dituitarv of rats are well worth noting: this assumntionwas confirmedbv the observationthat an inhibitorof PG svnthesiswas able to decrease botQ the TSH synthesisinduced bv TRH and the release Dromoted bv high K medium concentrations. The nroblem of direct interactionof PG with thvroid functionwas more carefullvstudied.NumerousAuthors have documenteda TSH like activitv of PGE : some of them used the increaseof adenvlcvclase activitv as a D.&meter of evaluation,some the increaseof c-AMP concentrationand some glucose oxidationan colloid droplet formation in equine (KANEKOet al. (15), ONAYA and SOLOMON (181, ZOR et al. (251, DEKKER and FIELD (18), AHN and ROSENBERG (II, FIELD et al. (ll), bovine (BURKE (4)) and sheeD (BURKE (5)) thvroid slices. In further exnerimentsAHN an ROSEMBERG (2) show for PGEl the caDacitv in stimulatingthvroxinesynthesisand % I-iodoproteins

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esence of perclorate; Droteolvsis in canine thvroid slices, even in however PGE does not reDroduce TSH effect on "P-incorporation into the DhosDho&ids of sheer, (BURKE (5)) or dogs (ZOR et al. (26)) thvroid slices. As for the other PGs' studied we remember the observations of BURKE (4) who documented for PGF the cauacitv to increase adenvlc+clase activitv and endoc%&?kain slices of sheep thvroid. Finallv the same Author demonstrated that such a PG was able to abolish submaximal TSH and LATS effects on thvroid glucose oxidation, suggesting the hvnothesis that TSH, LATS and PC&' may compete for common adenvlcvclase receptor sites in thyroid. At this point the possibilitv to transfer to humans what we found in exuerimental animals is quite difficult. In fact experimental literature on this DurDose is verv Door. However the possible interaction of PG with thvroid function in man is suggested bv indirect observations, such as those of WILLIAMS et al. (24) who found high PGE2 and PGF 2 alpha levels in venous vessels from thvroid medullary carcinoma.

MATERIAL and METHOD -19 healthv men, aged 16 to 45 vears, were studied. -PGF SuDDlied bv Upjohn ComDanv-Michigan was emDloved. -Con?&%% infusion (2,5mg/270 ml) was Derformed in 9 men with diluted in saline. Blood samoles -30, 0 and thereafter tt%a!gha minutes for a neriod of 270 minutes from onset of PG infusion for PRL, TSH, FSH, LH and GH radioimmunoassavs were collected from cubital vein via an indwelling Dlastic heparinized catheter. -In further exDeriments PGF Derfusions were performed 90 minutes before TRH injection (rate2ig$E!fon was Smcrgr/min in the first 30 minutes and lOmcrgr/min afterwards in a first experiment on 6 men: rate infusion was doubled in a second on 4 men). In the same subjects there was a three dav interval between TRH injection in basal conditions and that during PG infusion. Blood samoles were collected at -15,0,10,20,30,~5,60,90 and 120 minutes from endovenous injection of 200 mcrgr of TRH for radioimmunoassavs of PRL and TSH; T radioimmunoassav was performed at -15,0,60,90 and 120 minutes fram TRH injection in the first eweriment. -FSH, LH and PRL radioimmunoassav was performed with Biodata, GH and T with Cis-Sorin reagents: TSH levels were estimated with a radioi&nunological method using TSH Standard (amp. cod.68/30) supplied bv London National Institute of Biological Standards and Control, a soecific anti-HTSH serum (rabbit) supplied bv NIAMD (Bethesda) and goat anti-rabbit gamma-globulin as precipitating antiserum.

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-TSH and PRL incretorvareas are calculatedbv triangulationsystem.

RESULTS In a group of men a continuousPGF2 alp a infusion (2,&g/270 ml) was performed.As can be observed in Fig.1, tt: e behaviourof the TSH,W, PRL, FSH and GH mean levels shows no significantchanges. But if we consider individualsituationswe can point out some details which we consider to be noteworthy: LH and FSH pattern is caracterizedby episodicalincretorypeaks which reproducethe typical pulsatory behaviourdescribed in physiologicalconditions;as for GH we must remember that in 4 out of 9 observationsthe presence of,incretorypeaks at different times that. lose their evidence in the mean curve is documented.Finally while TSH levels are quite homogeneousin different subjects,PRL behaviouris more variabilebecause we found in one case out of 5 a huge increase of plasma levels in the last samples collected,accompaniedby parallel increase in GH levels. In a second experimentTSH and PRL incretoryareas after TRH injectionin basal conditionsare comparedwith those during PGF 2 alpha infusion.Fig.2 shows the comparisonbetween TSH response found in 4 men in basal conditionswith that during PGF infusion 2 alpha (lOmcrgr/min'l: hormone levels and incretoryareas are almost similar. However as for TSH response two men show ed differentbehaviour:in these, showing even in basal conditionsa TSH response at the highest levels of the normal range, a dramatic increase in the incrktory area was found during prostaglandininfusion ( fig.3 1. Prolactin incretoryareas on the contrarvwere quite similar in the six observationssvnthetizedin Fig. 4. infusion rate Thereafterin a similar experimentthe PGF was doubled and we found no change in the TSH and2PfiiD!%cretorv areas ( Fig. 5 et 6 1. Finally we compared the T thvroid response to endogenous TSH released by TRH injectionin3basal conditionwith that during PGF infusion ( Fig. 7 ). T mean plasma levels from 0 to 120 2 alphR minutes s ow no significantincre4se neither in basal conditionnor during PG infusion . On the contrary if we consider the mean peak response the increase is significantonlv when PGF infusion 2 alpha is performed.

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DISCUSSION infusion doesn't seem to interact ThereforePGF 2 glpha significantlvwith hyoot a amus-pituitarvhormone metabolism,at least with the doses used. On the one hand we can exclude a direct interactionwith TSH uituitarv section, because the onlv effect documentedbv us is a variable increase of GH, sometimestogetherwith prolactin:however the connectionof such a hormone increasewith PGF infusion 2 al&h Drolactin is quite uncertain.On the other hand the interactionwi and TSH resoonse to TRH is quite insignificant.In onlv two men a marked increase of incretorvarea was observed,for TSH but not for PRL; this demonstratesthat if we suggest a Dossible interactionof with hwothalamus-pituitarvaxis, this is identifiablein PGF 2 a Dha a modu1ation caDacitv of Dituitarvcells resDonse to TRH and not in a releasingeffect on the pituitarv. interferenceorathvroid response The finding of a PGF 2.plpha to endogenousTSH is more sign1 icant; in fact the T increase is statisticallv significantwhen we consider the T Q 2ak responses. This would seem to be in agreementwith the exper?mentalobservations of previouslvreported literaturewhich while consideringa PG interaction on TSH pituitarv axis, unikelv shows a richdocumentation of Dossible direct effect on the thvroid gland. As for mechanism of action this PG could plav the role of an eventual third messengermediated between hormone and $,5 c+AMP witl,+_the sDecificeffect of modulatingthe membrane Na , K and Ca flux, absolutelvnecessary to activate adenvlcjrclase. This hvpothesiswhich is more valid for the internretationof TSH thvroid stimulation, could even be reseated,with less evidence,for releasinghormones pituitarv activation. Eventuallvwe can't exclude that the effect mav be mediated bv a change in the vascular bed, that looks uarticularlvaffected bv such a prostaglandin,especiallv for TSH thvroid stimulation.

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REFERENCES 1.

Ahn, C.S. and I.N. Rosemberg. Jodine metabolism in thvroid slices: effects of TSH,dibutvrvl cvclic 3,s AMP, NaF and PGE . 1 Endocrinologv 86:396, 1970

2.

Ahn, C.S. and I.N. Rosemberg. Proteolvsis in thvroid slices: effects or'TSH, dibutvrvl 3,s AMpc and PGE1. Endocrinologv 86:

870, 1970 3.

Amoss, M.,R. Blackwell, W. Vale, R. Burgus and R. Guillemin. Stimulation of concomitant secretion in vitro of LH and FSH bv hvglv purified hwothalamic LRF: evidence for a prostaglandin receptor for the release of LH. Inter. Con@. Phvs. Sci. 9: 175(Abst.371 1971

4.

Burke, G. Effect of iodide on thvroid stimulation. J. Clin. Endocr. Metab. 30:76, 1970

5.

Burke, G. On the role of adenvl cvclase activation and endocvtosis in thvroid slice metabolism. Endocrinologv 86:

353, 1970

308

6.

Burke, G. Effects of PGs' on basal an stimulated thvroid function. American Journal of Phvsiologv 218:11$5, 1970

7.

Burke, G., K. Kowalskv and D. Barbiartz. Effect of thvrotronin, PGEl and a PG-antagonist on iodide trapping in isolated thvroid cells. Life Sciences 10:513, 1971

8.

Dekker, A., J.B. Field. Correlation of effects of thvrotropin nrostaplandins and ions on glucose oxidation, cvclic AMP and colloid droplet formation in dog thvroid slices. Metabolism 19:$53, 1970

9.

DeWied, D., A. Witter, D.H.G Vesteeg and A.H. Mulder. Release of ACTH bv substances of central nervous svstem origin. Endocrinologv 85:561, 1969

10.

Drouin, J.and F. Labrie. Effects of PGs' on hormone release bv adenowhonhvseal cell in culture. Abstracts of Inter. Conf. on PGs'. Pas. 85, Florence 1975

11.

Field, J., A,.Dekker, U. Zor and T. Kaneko. In vtro effects of PGs' on thvroid gland metabolism. Ann. of the New York Academv of Sciences 180:278, 1971

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12.

Harms, P.G. Prostaglandin involvement in hwothalamic control of gonadotropin and prolactin release. Science 18:760, 1973

13.

Hedge, G.A. Effect of cvclic AMP and prostaglandins on ACTH secretion.-Intern. Congr. Phvs. Sci. 9:211(Abst.709), 1971

14.

Ito,H., G. Momose, T. Katavama, H. Takagishi, L. Ito, H. Nakajima and Y. Takei. Effects of arostaglandin on the secretion of human growth hormone. J. Clin. Endocrin. Metab. 32:857, 197.1

15.

Kaneko, T., U. Zor and J.B. Field. Thvroid stimulating hormone and PGE stimulation of 3,s AMPc in thvroid slices. Science 163: 1062, 1469

16.

Macleod, R.M. and J.F. Lehmever. release of nituitarv growth hormone bv prostaglandin and dibustvrvl adenosine cvclic 3’-5’ monophosnhate in the absence of protein svnthesis. Proc. Natl. Acad. Sci. 67:172, 1970

17.

Ojeda, S.R. Central effect of PGE1 on prolactin release . Endocrinologv 96:613, 197.4

18.

Onaka, T. and D.A. Solomon. Stimulation bv PGE1 of endocvtosis and glucose oxidation in canine thvroid slices. Endocrinologv 86: 423, 1970

19.

Penp, T.C., K.M. Six and P.L. Munson. Effect of PGE on the hvnothalamus hwonhvseal-adrenocortical axis in rat:. Endocrinologv 86:202, 1970

20.

Pharris, B.B., L.J. Wvngarden and G.D. Gutknecht. Biological interactions between prostaglandins and luteotropins in the rat. In Gonadotropins(Proc. Workshop Conf.) E. Rosenberg (Ed.) oag. 121, Geron-x, Los Altos, Calif. 1968

21.

Sato, T., T. Jvjo, T. Iesaka, J. Ishikawa and M. Igaraschi. Follicle stimulating hormone and orolactin release induced bv prostaglandins in rat. Prostaglandins 5,483, 1974

22.

Schofield, J.G. PGE1 and the release of growth hormone in vitro. Nature (London) 228, 179, 1970.

23.

Vale, W., C. Rivier and R. Guellemin. A "prostaglandin receptor" in the mechanisms involved in the secretion of anterior pituitarv hormones. Federation Proceedings 30, 363, 1971

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24.

Williams, E.D., S.M.M. Karim and M. Sandler. Prostaglandin secretion bv medullarv carcinoma of the thvroid. Lancet I: 22, 1968

25.

Zor,U., T. Kaneko, I.P. Lowe, G. Bloom and J.B. Field. Effect of TSH and PGs' on thvroid adenvl cvclase activation and cvclic 3’-5’ AMP. Journal of Biological Chemistrv 241:5189, 1969

26.

Zor, U., T. Kaneko, H.P.G. Schneider, S.M. McCann and J.B. Field. Further studies of stimulation of anterior uituitarv cjclic adenosine 3’-5’ mononhosnhate bv hvnothalamic extract and PGs'. J. Of Biological Chemistrv 245:2883, 1970

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9 8 7 t

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Fig. 1

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The figure illustratesthe effect of a continuous infusion ( 2,$4q'27Omin) on TSH, PRL, LH, FSH and GH of PGF nlasma21~~~. No significantchange is shown.

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Fig. 2

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The figure shows the comnarison between TSH resnonse found in four men in basal conditions and that during PGF 2.alnha infusion ( 10 mcrgr/min\: no sipnificant difference IS evident.

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Fig.

3

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LG.

The figure shows the behaviour of TSH resnonse to TRH of two men in basal conditionsand that during PGF 2 alnha infusion ( 10 mcrgr/min~: a significantincrease is documented during PGFZ alnha infusion.

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The fipre shows the comvarison between PRL resoonse found in four men in basal conditions with that during infusion ( 10 mcrgr/min): the incretorv areas PGF 2 Tlnha are a most similar.

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The figure shows the comnarisonbetween TSH response found in four men in basal conditionswith that during infusion ( 20 mcrgr/min):no significant PGF is observed. dif1ea,l,",&

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Fig. 6

316

The figure shows the comnarisonbetweenPRL resoonse found in four men in basal conditionsand that during infusion ( 20 mcrgr/minj:no significant PGF dif%e%$% is observed.

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The figure shows the comparison between T increase 3 after TRH injection in basal conditions and that during infusion (10 mcrgr/min): if we consider the PGF 2 alnka mean oeax resnonses the rise is significant, but onlv infusion is performed. when PGF 2 aloha

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Possible interaction of PGF2 alpha with hypothalamus-pituitary-thyroid axis in man.

PROSTAGLANDINS POSSIBLE INTERACTIONOF PGF WITH BVPOTHALAMUS-PITUITARY2 alpha THYROIDAXIS IN MAN. G. Valenti,. G.P. Ceda, E. Tarditi, P. Chiodera, V...
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