Life Sciences Vol. 14, pp . 237-246, 1974 .

Pergemon PressPrinted in Great Hrltain

èIa1IR8iTIEiP

BYl+~ATSETIC REGULATION 0f THYROID HOdtl~AE BHCRSTIOII

Aras Nalander, Lacs E. Ericsoa, sad Frank Bundler

Division of Clinical Pte="+-~ology, DepartmeaL of Pharmacology, University ofLundi Departaert of Anatomy, University of Göteborg; and Departaent of Histolo-gy, University of Luad; Lund sad Göteborg, Bvadea .

(Received in final form 13 November 1973)

The interrelations of the sympathetic-adreaergic system and the ttprroid

gland have been subject to twCh clinical sad e~rperimertsl inttrest (1-15) . Long

before the discoveries of epinephrine and norepinephriae a,s sympathetic messen

gars, iL vas suggested that the syaptoms of hyperthyroidisa night be related to

overactivity is the aympathetfc nervous system (6, 1T), and it is yell known

that there is s close similarity between the effects of catecholmines sad the

signs of hyperthyroidism (6, 10, 15, 16) . Pathologic alterations of sympathetic

structures is hyperthyroid patients have been described, and the division or

removal of cervical sympathetic nerves has been used ss s treatment of hyper-

thyroidism (6, 1T) . This therapeutic approach vas relinquished long ago (6),

but anti-adrenergic drugs, auch as reserpine, guanethidine and adrenergic block-

ing agents, are nowadays used in the preparation of hyperthyroid patients for

thyroidectaaq and in the treatment of thyrotozic crisis (6, 10, 15, 16, 19-22) .

However, experiaental studies carried out in order to elucidate the intarrels-

Lions of sdrenergic activity and thyroid function have yielded controversial

results . Both stiaulatory and inhibitory effects of sympathetic stimuli and cs-

techolaaines on thyroid activity have been reported, (2-4, 6, T, 9, 10, 12-14,

23-25) and a caoroa opinion is that the sympathetic-adrenergie influence on the

thyroid is restricted to effects oa glandular blood flow (2-T, 11, 26) .

A possible reason for the divergent results and interpretations easrges

from the recent observation that the nuaber and distribution of sympathetic ner-

237

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Sympathetio-Thyroid Regulation

Vol. 14, No . 2

ves within the thyroid varies extreme],y between species (see below) . Another

reason is inferred isram the complex interactions displayed between cstecholn-

mints, TSft, and thyroid hormone(s) : Cntacholamines can induce secretion of thy-

road hormone (2, 14, 23-25), but it is not certain that this is recorded by

measurements of the plasma levels of thyroid hormone since cstecholemines may

also enhance the turnover of thyroid hormone (2, 6-8, 2T-29 ). In addition, ca-

techolemines mssy influence the accretion of TSH, and entecholamiae-induced

changes is blood flow msy alter the distribution oP TSH to, as well ns the out-

flw of thyroid hormone from, the thyroid gland (3, 4, 6, 11, 14, 30) . Even

more significant is the fact that exogenous catecholemines and TSft can exert

both additive and mutually antagonistic effects on thyroid hormone secretion,

depending on the timing of administration of the compounds and on the are-ndmi-

niatration state of thyroid activity (30) . Therefore, to evaluate the possible

influence of sympathetic stimuli on thyroid hormone accretion, the degree of

TSH exposure must be controlled, and it is necessary to know the type and dist-

ribution of the sympathetic innervation of the thyroid to be studied. In addi-

tion, it is advisable to examine not only the plasma levels of the hormone but

also the secretioy process as such, i .e . the endocytoeis of thyroglobulin and

subsequent intracellular events .

The combination of fluorescence histochemistry and electron microscopic nu-

toreàiography hss permitted detailed studies of the number and distribution of

thyroidal adrenergic nerves . Ia the thyroids of several species, including man

(Melander et sl., to be published) and mouse (13, 31, 32), norepinephrine-con-

taining serve fibers are present not only as a netwrk around vessels, but nu-

merous fibers running between and around follicles have also been demonstrated

(Fig, 1 n) . Hoth types of fibers disappear after surgical or chemical (6-hvdroxy-

dopamine-induced) aympnthectoely (31, 32 ; Fig . 1 b), and hence Lhey sre classi-

fied ae sympathetic, post-ganglionic adrenergic nerves . Electron microscopic

nutoradiogrnphy of thyroids from 3H-norepinephrine-injected mice (32) as well as

Vol . 14, No . 2 Sympathetio-Thyroid Regulation

239

of hmnan thyroid slices incubated with 3R-norepinephrine (Melaader et al., to

be published) reveals that the interfollicular sympathetic fibers have terminals

that are located very close to follicle cells, only the follicular basement bae-

brave intervani:ig (32, Melander et sl., to be published ; Mg . 2) .

FIG. 1

Fluorescence photamicrographa (z 200) of sections from a thyroid of a mousewith a left-side cervical sympathectomy (the superior cervical ganglion hadbeen removed 10 days previously) .a) Right thyroid lobe . Formaldehyde-induced green fluorescence, due to presenceof norepiarphriae (~3), in nerve fibers occ~ring both as a network aroundvessels and as single fibers clone to follicles. b) Left thyroid lobé . Completeabsence of norepinephrine-containing nerve fibers after left-side sywpathectcaq .

240

Sympathetio-Thymid Regulation

Vol. 14, No. 2

FIG. 2

Electron microscopic autorsdiograph (x îb,000) of s section li~o~m n normal humanthyroid incubated in 3H~norepfnephrine . FC : thyroid follicle cell . FL : folliclelumen . Autoradiographic silver grains, indicating the presence of (radioactive)norepinephrine, are mainly found over nerve terminal (T), located close to thefollicle cell .

Vol. 14, No. 2

Sympathetio-Thyroid Regulation

241

Tha nustber of interfollicular sympathetic fibers shove s very Barked varia-

tion between species : in contrast to the findings fn man and mouse, iatertolli-

cider sympathetic fibers are sparse is the thyroids of rats, dogs (9uadler,

unpublished) end calves (33) . Renee it seems likely Lhst inter-species varia-

tion may account for soave of the discrepant results of preview studies, which

have been carried out on several different species (2-T, g-14, 2}25) . In

edditioa, studies in progress indicate that there wY also be a variation With

ages thyroids of one-year-old mice have very !ew histochemically detectable

interfollicular sympathetic fibers, in contrast to the above-~eationed findings

fn lounger (b-12 weeks old) animals.

Tha finding of syaa~athetic nerve terminals very close to thyroid lbllicle

cells signifies that there ie a morphologic basis for a direct, aoa-~rucular,

inflwnce of sympathetic stimuli on thyroid hormone secretion (31, 32 ) . There

is also evidence that such sn influence is exerted : In mice, whose TSR secre-

tion has been eliminated, sympathetic stimulation or administration of nor-

epinephrine (11S) or other arylethprlamiaes induces secretion of thyroid hotness,

se reflected by signs of endocytosis of thyroglobulin followed by release of

thyroidal radioiodine into the blood (14, 2}25, 31i Fib" 3) . The secretioy res-

posse to sympathetic stimulation is restricted to the thyroid regions supplied

by the stimulated nerve, indicating that the effect results fre® as action of

1fE released within the gland (31 ) . The thyroid activation is probably induced

by the aaine(s) u such: the effect is augs~ented after pretraats:ent rith a.aono-

aaine oxidsse inhibitor, sad the catecholsmiae precursor DOPA a:arts a thyroid-

-etimulatiag effect only after its deearboxylstion to dopamine (22). Although

csteeholamines certsia~r affect thyroid blood flow (3-T, 10, 11), their stimu-

latory effect oa thyroid bombes secretion ca,anot sratirelse be ezplaiaed by their

inflwnce on thyroid vessels; it is rather the result of a direct action on the

follicle cells (ld, 24, 29) . Indeed, 11E sad other catecholsaiaes have bees shows

to stimulate the iacarporatioa of iodise sad the synthesis of thyroid horasone

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Sympathetio-T6yroid Regulation

Vol. 14, No . 2

in isolated thyroid cells (12, 13, 33) " Alpha or beta adreaergic blocking drugs

can abolish the thyroid-stimulating effect of the catecholamines but not that of

TSH, whereas the drug polyphloretia phosphate inhibits the response to TSH but

augments or does not affect that to the catecholamines (24, 25, 34) . Therefore,

it appears likely that the initial actions of TSH and NE on the follicle cells

involve different receptors ; however, the subsequent intracellular reactions mevy

be similar and they include stimulation of adenylate cyclase and formation of

cyclic A1~ (12-14, 24, 30, 34) .

ifoo _

Too _

600 _

900 _

FZG . 3

alood ..aowdln . Ntel (Yeen * SEN)

x ot Innlel .a~e

Unilot NE E IPNE DA 6-NT NeCIept O.oe O.oe Oao 4a toetlm

H1ood radioiodiae levels is 125I-injected, thyroxine-treated lice after unilate-ral electrical syupathetic stimulation (uailat apt sties) or single intravenousinjections of Irnorepiaephriae (1fE), Irepinephrine (E), Irisoproterenol (IP1fE),dopsaine (DA), 5-hydrwgrtryptamine (5-i1T), or 0.9 x sodium chloride (NaCl) .Blood samples (100 /~].) were ta><en ims~ediately before and two hours after treat-ment .

Vol . 14, No . 2

Sympathetlo-Thyioid Regulation

243

In order to further evaluate the physiological significsnce of the sympa-

thetic nervous system in the regulation of thyroid hormone secretion, efforts

have been made to determine whether the secretion is affected by withdra~+al o!

tonic sympathetic support in mice with as intact TBH secretion (32 ) . In such

unseals, sympathectasgr appears to evoke a aoderate and short-lived reduction in

the blood level of thyroid hors~oae. As sympathetic stimuli and catecholamines

can enhance thyroid hormone turnover (6-8, 2T, 28) and ss syapathectoegr rather

reduces Lhan increases the distribution space of the hormone (Flelaader, u~ub-

lished), ft is most likel3r that the sy:pathectamp~-induced reduction in the blood

level of thyroid ~rmone results irce a diminished secretion of the hormone (32 ) .

Since TBH secretion was not eliminated in these animals, it cannot be complete-

ly excluded that the diminished secretion of thyroid hormone wan secondary to

catecholamiae - TSH interactions of Lhe kind described in Lhe introduction (cf

30 ) . Aowaver, the most probable usuaption is that the sympathectougr-induced

cessation of 1fE release from interfollfcular sympathetic terminals causes a re-

duction of Lhyroid hormone secretion (32 ) . The short duration (1-2 days) of this

reduction is probabler due to a compensatory increase in TSH secretion (32) .

Ia conclusion, thyroid follicles in the mows are in close contact with

sympathetic, adreaergic fibers which allow the sympathetic nervous system to

ucert a direct influence oa the secretion of thyroid hormone . The tonic sympa

thetic iariuence ~ be slight, but ayapathetic activation can profoundly en-

hence thyroid hormone secretion . This constitutes a mechanism for rapid adapta-

tion. of thyroid hormone secretion to appropriate physiological stimuli (32 ) .

Recent studies indicate that a similar mechanism ma, operate in man . ks

mentioned and shorn above, the human thyroid contains maerow iaterfollicular

sympathetic fibers, with terminals located close to the follicle cells (Melan

der rE al., to be published ; iris . 2) . Ia addition, the human thyroid appears to

respond to sympathetic stimuli : imubation of human thyroid slices with cate-

cholsmiaes enhances endoeytosis of thyroslobulin (Melaader et s1 ., to bs pnb-

fished) and release of thyroid hormone (Damont, personal comsmnieatioa) . Thus,

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Sympathetio-Thymid Regulation

Vol. 14, No. 2

there is aorphologic and functional evidence that the sympathetic nervow sys-

tea may exert a direct, stimulatory influence on thyroid hormone secretion is

mss.

The existence of such an inflwnce would justify re-introduction of the

old hypothesis that as increased eys~sthetic activity asy be iavolnd is the

denlopaert sad/or maintenance of hyperthyroidism. This hypothesis seed not

contradict the concept of hyperthyroidism as a genetic-immurwlogic disorder

(35-40) . Für examplq there are several indications that emotional and (other)

stressful stimuli say precipitate hyperthyroidism in patients with a predispo-

sition to it (36, 41) ; this triggering effect could be mediated by the 8ymps-

thetic aervow systea, vherssfter genetic-i+~ .++~±logic factors maiatsia the

disease . It is also possible that as already hyperthyroid state msy develop in-

to a thyrotouic crisis by sn abrupt increase in the flow of sympathetic stimuli

to the thyroid . This possibility gets support from the fact that anti-adreaergic

drugs, such as reserpine, gusnethidine sad adrenergic blocking agents, are

efficient tools in the treatment of thyrotoxic crisis (6, lo, 15, 16, 18-22) .

Anti-adrenergic drugs have beneficial effects also in milder forms of hyper-

thyroidism ; iadead, p~ropranolol can be wad as the sole drug in the periopera-

tin management of hyperthyroid patients undergoing thyroideet~ (22) . These

findings indicate the possibility that anti-adrenergic drugs can alleviate sours

of the symptoms of hyperthyroidisa by reducing as increased sympathetic tone oa

thyroid follicles and vessels . Whether or sot this is correct, anti-adreaergic

drugs wY interfere with the metabolism and/or effect of thyroid bosons ; the

latter is a prevalent view (6, 10, 15, 16, 18-22, 42) .

Ia coaciwioa, the sympathetic aervow system asy hen a direct inflwnce

oa the secretion of thyroid horaooe is mss, sad it aswy also modulate the aetabo-

lim and/or effect of the ha~rmone . It is possible that an increased sympathetic

activity can precipitate hyperthyroidism sad/or sugs~sat the s>~tasts of this

disease. This vonld provide a pharmacoQyaasic basis for the we of anti-adrener-

gio drugs in hyperthyroidiss.

Vol . 14, No . 2

SympathetiaThqroid Regalatioa

245

Acknowled~eat

Some of the imeetigations revieved herein have been supported by Ornat

No . B74-04X-3880-02 lYom the Svedfsh Medical Reeaarch Council .

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