812 SEPT. 29, 1962

SPERMATOZOA*BY

Lord WIOTHSCHILD, Sc.D., F.R.S.Department of Zoology, University of Cambridge

Sperm MetabolismApart from undertaking minor repair jobs of the smallcountry-garage type, sperm metabolism is concernedwith the provision of energy for movement through thesynthesis and breakdown of adenosine triphosphate"(A.T.P.), which, when hydrolysed by the' enzymeadenosine triphosphatase, already mentioned as beingpresent in the sperm tail, provides or transfers thenecessary free energy for movement. When, therefore,one examines the metabolism of spermatozoa bymeasuring their oxygen uptake, their lactic acid produc-tion, rate of fructose utilization, heat production, orcarbon dioxide output, one is measuring an activitywhose purpose is the synthesis of A.T.P. to counter-balance the loss incurred during movement. If thisstatement is correct, there should be a correlationbetween the various indices of sperm metabolisnmmentioned above and A.T.P. concentration. It is easiestto examine this question under anaerobic conditions-that is, in the absence of oxygen. In these circumstancesmammalian spermatozoa utilize the carbohydratefructose, secreted into the seminal plasma by the maleaccessory organs, as a source of energy. The overallreaction is

fructose + 2A.D.P. + 2H3PO4, 2 lactic acid +2 A.T.P. + 2-H20, AH = -27.7 kcal.

During this reaction 1 mole of fructose is broken downto 2 moles of lactic acid, and 2 moles of adenosinediphosphate (A.D.P.) are converted to 2 moles ofA.T.P.The hydrolysis of 1 mole of A.T.P. to A.D.P. releases

about 7 kcal. of free energy. How does this amountof free energy compare with what a spermatozoon needsfor movement ? One millilitre of bull semen contains109 spermatozoa, which, in the absence of oxygen, breakdown 2 mg. or 11.1 micromoles of fructose per hourat 370 C. This means that 22.2 micromoles or 11.26 mg.of A.T.P. is synthesized at the same time. This isequivalent to 6.1 X 10-18 moles A.T.P. per spermatozoonper second, or 18 x 10-7 erg per spermatozoon persecond. By examining the hydrodynamics of spermmovement, which is an exercise in applied mathematics,an estimate can be made of the energy a bull sperma-tozoon expends in swimming at its normal speed of100 ,U per second. The value is 2 x 10-' erg per second,so that about nine times as much A.T.P. is synthesizedduring the anaerobic metabolism of bull spermatozoaas is needed for movement. One might therefore expectthat the concentration of A.T.P. should increase duringthe anaerobic incubation of bull spermatozoa. This,however, does not occur, as shown in Fig. 7, in whichthe anaerobic heat production, the impedance changefrequency, and A.T.P. concentration in bull sperma-tozoa are compared. The heat-production curve,labelled H, falls for the first 100 minutes; it then remainssteady for a further 100 minutes, after which it falls tozero. Except at the end of the experiment, the change

SThe second part of the Ingleby Lectures delivered at theUniversity of Birmingham, March 15 and 16, 1962. The firstpart appeared in last week's issue.

in A.T.P. concentration shows little or no relationshipwith heat production. Even worse, if that is the rightword, is the relationship between impedance changefrequency-which, it will be remembered, is a goodindex of sperm activity-and heat production or A.T.P.concentration. The impedance change frequency fallsto zero just at the time when the heat production startsits second, constant, phase. The relationship betweenA.T.P. concentration and impedance change frequencyis more or less non-existent. When such contradictionsoccur, the first move is to re-examine the basic assump-tions. The first of these is in the overall equationgiven above. Are 2 moles of A.T.P. synthesized permole of fructose broken down to lactic acid ? Experi-ments to verify this widely accepted assumption presenta number of difficulties.The breakdown of fructose to lactic acid provides the

energy for movement. Is the measurement of heatproduction just a sensitive way of measuringfructolysis ? If so, when spermatozoa break down 1mole of fructose to 2 moles of lactic acid, 27.7 kilo-calories of heat will appear in a calorimeter. This canbe tested by measuring the amount of fructose meta-bolized by a suspension of spermatozoa, and comparingthe expected heat of combustion of this amount offructose with the actual amount of heat produced by thesame suspension. In ten experiments the averageexpected amount of heat during one hour was 524millicalories and the actual amount of heat producedwas 423, about 20% less. Where did the lost heat go ?One explanation may be that bull spermatozoa do notconvert fructose stoichiometrically to lactic acid.Curiously enough, comprehensive information on thiselementary point is not available.

If nine times as much A.T.P. is produced duringanaerobic fructolysis as is needed for sperm movement,why does the concentration of A.T.P. go down and notup ? One possible explanation concerns the amount ofenergy a spermatozoon dissipates while swimming.Hydrodynamic calculations are unlikely to be veryaccurate, and in any case they cannot at the moment

Time (min.)FIG. 7.-Variations with time in anaerobic heat production (H),impedance change frequency (i.c.f.), A.T.P., and A.D.P. of bull

semen.

BRITISHMEDICAL JOURNAL

SPERMATOZOA

on 8 July 2020 by guest. Protected by copyright.

http://ww

w.bm

j.com/

Br M

ed J: first published as 10.1136/bmj.2.5308.812 on 29 S

eptember 1962. D

ownloaded from

SEPT. 29, 1962 SPERMATOZOA BRITISH 813MEDICAL JOURNAL

take account of the effects spermatozoa have on theenergy dissipation of their neighbours. It is likely thatin a suspension containing millions of spermatozoa inclose proximity any particular spermatozoon wi-ll haveto expend more than the expected amount of energy to

keep moving at its nornial speed. In simple language,spermatozoa increase the viscosity of the medium inwhich they are suspended and therefore have to

work harder to keep going, assuming they do keepgoing.

Though it is more or less certain that thedephosphorylation of A.T.P. is responsible for sperm

movement, that A.T.P. is synthesized during fructolysis,that sperm heat production is associated with theirmovement and fructolysis, and that impedance changefrequency is a measure of sperm movement, when one

tries quantitatively to examine the interconnexionsbetween those properties of spermatozoa, a number

of loose ends andquestion-marks appear.

G-C Further experiments are~~~~needed.

Sperm Heat ProductionS. The measurement of

sperm heat production

p5. ainvolves microcalorimetry,because spermatozoa pro-duce small amounts ofheat, millicalories or

microcalories that is,thousandths or millionths

llfA. of a calorie-per second.

My calorimeter involves

the use of thermocouples.When pieces of constantan

and copper wire arejoined together and thereis a difference of 10 C.between the join and the

a.other end of the copperwire, a voltage differenceof 40 microvolts-that is

to say, 40 millionths of a

volt-is developed. If

litO|111''.B there are two junctions,the voltage difference

is 80 microvolts. Onecannot have as many junc-

_ C tions as one likes, forcertain technical reasons.In this calorimeter thereare 80. The calorimeteritself is shown in Fig. 8.About 2.5 ml. of spermsuspension is plac.d inthe top inner glass tube.The bottom tube is a com-

pensating vessel to take2-3cm care of any stray tempera-

ture changes there may beFIG. 8--Calormeter. G.C., round the calorimeter.glass capillary, G.S., glassstopper; P., polythene collar; The thermocouples areA., araldite; G.T., glass tube embedded in glue andcontaining biological material;B., brass tube; Ga., leads from wraped round the glass

thermopile tb galvanometer; tube. In addition to thec.i9., outer brass tube; C., compensaing vessel justcompenisating chamnber'.

mentioned, elaborate arrangements have to be made tomaintain the temperature as constant as possible roundthe calorimeter. The variations in temperature in mylaboratory, in the outer container of the calorimeter, andof the calorimeter itself when there is no biologicalmaterial in it but just distilled water, are shown in Fig. 9.It will be seen that the room temperature is given indegrees centigrade, that of the outer container inthousandths of a degree, and that of the calorimeteritself in millionths of a degree, which gives some idea ofthe sensitivity of the equipment and of the stabilityneeded to do this type of experiment.The curve labelled I in Fig. 10 shows the anaerobic

heat production of bull semen, while the curve labelledIII shows the anaerobic heat production of the same bullsemen diluted 1:3 with Ringer solution. Thedotted curve (II) is unimportant in this context, beingconcerned with the accuracy of the recording apparatus.Bull spermatozoa utilize fructose, present in the seminalplasma, as a source of energy for movement underanaerobic conditions. In this experiment the heatproduction of the bull semen (curve I) fell dramaticallyafter 153 minutes. This was not due to all the fructose

2120

864

x 2

16-8

,o 11.21 15

x 5-6

'1I0 200

Time (min.)400

4

_,_

064 E

132 EE

FIG. 9.-Temperatures of (a) room, (b) outer calorimeter bath,and (c) calorimeter.

Time (min.)FIG. 10.-Anaerobic heat production per unit number ofspermatozoa. I, bull semen; Ill, bull semen diluted 1:3 withdiluent. (The dotted curve, 11, is concerned with the accuracy

of the recording apparatus.)

-a~ ~ ~

-c~~~~~~~~~~~~1C~~-op~Awj

b~_ _

on 8 July 2020 by guest. Protected by copyright.

http://ww

w.bm

j.com/

Br M

ed J: first published as 10.1136/bmj.2.5308.812 on 29 S

eptember 1962. D

ownloaded from

814 SEPT. 29,1962 SPERMATOZOA~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~having been used up in the external medium, but to theseminal plasma becoming too acid to support movement,because of the production by the spermatozoa of lacticacid. The two curves, I and III, are scaled to the same

number of spermatozoa, so that the spermatozoa afterdilution produce heat at a markedly higher rate thanthe undiluted ones. Why ? One explanation concerns

the development of acidity in the medium when thespermatozoa are concentrated. When bull semen is

diluted with a buffered physiological diluent, not only isless acid produced, because there are less spermatozoa,but also the medium's buffer capacity is greater than thatof seminal plasma; the pH therefore falls less. There is,however, another possible explanation, that spermatozoaswim more actively, and therefore dissipate more heat,in a dilute suspension. One reason why they mightswim more actively is because the suspension as a wholeis less viscous. But this argument implies that whenspermatozoa are in a viscous medium they somehowrealize that the medium is viscous and therefore do nottry so hard. Experiments to verify this possibilitywould be of interest.

Fig. 11, top half, is a comparison of the anaerobic heatproduction of bull and human spermatozoa, scaled tothe same number of cells. The heat production ofhuman spermatozoa is more than double that of bullspermatozoa. The bottom half of Fig. 11 is a comparisonof the anaerobic heat production of bull and humansemen. The reason why the bull semen has a greaterheat production than human semen is because it containsabout ten times as many spermatozoa per ml. The

b

4u ~~~~IVN; 40FOn=-M

':'-~-S0N

0

E

co

02

E X_ r

0 40 80 120 160

Time (min)FIG. 11.-Anaerobic heat production of: I, human semen; II,

human seminal plasma; Ili, bull semen; IV, human spermato-zoa; V, bull spermatozoa.

dotted curve labelled 11 is of interest. This is the heatproduction of human seminal plasma, which represents

more than half the total heat production of humansemen. The heat production of bull seminal plasma isnegligible. This difference between human and bu.lseminal plasma is probably due to the hydrolytic break-down in human seminal p'asma of phosphorylcholine,by acid phosphatase, to choline and orthophosphate.The reaction does not occur in bull seminal plasma.

Sperm ModelsSo-called sperm models are prepared by extracting

spermatozoa, which means subjecting them to a

physiological solution such as phosphate buffer.containing in addition versene, thioglycollate, anddigitonin. Extraction destroys the cell membrane of thespermatozoon and removes all soluble enzymes, organicand inorganic compounds. Bull spermatozoa stopmoving within ten seconds of applying the extractionmedium, though under the light microscope they appear

to be morphologicaily normal. However, as might beexpected considering what has happened to them, theydo not consume oxygen; nor do they fructolyse ormove. If the extraction medium is replaced by one

which does not contain versene, thioglycollate, or

digitonin, but does contain calcium and A.T.P., the tailsof bull spermatozoa exhibit rhythmic activity-that is tosay, they bend from side to side at about the same

frequency as in live spermatozoa. These bending waves

are not, however, propagated along the tails, which iswhy the spermatozoa do not move forward. This means

that extraction does not interfere with the A.T.P.-dephosphorylating enzyme, adenosine triphosphatase,nor with the machinery, whatever it may be, forconverting the free energy made available during thedephosphorylation of A.T.P. into the mechanicalcontraction of the fibrils in the sperm tail. At the same

time extraction destroys the system inside the spermtail which instructs successive segme-nts of the tail fibrilsto contract and relax in a particular ocder at particulartimes. This system, which a number of gametologistsfeel is, or is in, the centriole, should therefore be absentin extracted spermatozoa, which suggests that an

electron-microscope study of extracted spermatozoamight be rewarding in identifying the control system.by its absence in comparison with normal spermatozoa.

RheotaxisObjects whose length is great in comparison with their

width, such as a long molecule or a tree-trunk, exhibitflow orientation, or rheotaxis, in a stream of liquid, or,as it is technically called, a fluid velocity gradient.Such objects align themselves with their long axes

parallel with the direction of fluid flow. The velocitygradient is mentioned because the velocity at whichwater flows along a glass tube varies from zero whereit is in contact with the glass walls to a maximum atthe centre of the tube. The rheotaxis, or flow orienta-tion, of long molecules or tree-trunks is only due tothe velocity gradient-that is, to the streaming velocityvarying at different positions in the tube. Some animals,however, not only exhibit the physical phenomenon offlow orientation but also swim preferentially up (ordown) stream. To do this, one might think that an

animal must have organs or apparatus which enableit to know which way the stream is flowing. Salmon,for example, have eyes with which they can see objects

BRITISHMEDICAL JOURNAI814 SEPT. 29, 1962 SPERMATOZOA

on 8 July 2020 by guest. Protected by copyright.

http://ww

w.bm

j.com/

Br M

ed J: first published as 10.1136/bmj.2.5308.812 on 29 S

eptember 1962. D

ownloaded from

SEPT. 29, 1962815BRITISH

MEDICAL JOURNAL

in the water or on the river bank; they also have semi-circular canals which react to angular and, possibly,rectilinear accelerations or decelerations; in addition,fish have a special organ, the lateral line system, whichis sensitive to water movements relative to the fish.These are sense organs which enable a fish to respondto the flow of water past it. So far as we know, sperma-tozoa have no sense organs, and it is therefore hard tobelieve that they swim upstream, which was asserted onseveral occasions in the nineteenth century but waslater disputed. Contrary to what a number of peopleintuitively feel, if you are thrown into a flowing riverin the dark without special equipment, you cannot tell,once you start swimming, whether you are swimmingwith or against the current. How, then, do spermatozoaswim upstream, or exhibit positive rheotaxis as it iscalled, which I have recently satisfied myself they do ?

Experiments were started with dead bull spermatozoa,using vertical parabolic velocity gradients. It is quiteeasy to arrange that the velocity gradient is only verticalby using a glass tube shaped like a very shallow boxand restricting observations to the middle. As expected,dead spermatozoa exhibited flow orientation becausetheir length is great in comparison with their width;but instead of the orientation being random--that is tosay, half the sperm heads pointed in one direction,upstream, and half in the other direction, downstream-it was surprising to find that all the spermatozoa pointeddownstream in the top half of the tube, whereas all thespernmatozoa pointed upstream in the bottom half. Thiscan be explained. First, a dead bull spermatozoon hasa greater specific gravity than its normal suspendingmedium and therefore sinks. Secondly, the head, beingpacked with deoxyribonucleic acid and being morecompact than the tail, sinks more quickly than the tail.(In time all dead spermatozoa in a stationary suspensionmay be seen to be pointing vertically downwards, headfirst.) It is because dead bull spermatozoa slowly sinkhead first that in a vertical parabolicvelocity gradient they have such apeculiar distribution, pointing dowNn-stream in the top half and upstream in >the bottom half of the system. Fig. 12explains diagrammatically why thishappens. The heads of the spermatozoain the top half are in regions of higherstreaming velocity than the tails, and i"therefore get pushed forward faster.In the bottom half, however, the tails \are in regions of higher velocity than theheads, so that they get pushed forwardfaster than the heads.

If a dead spermatozoon sinks head first,because of the previously mentionedproperties of the head, one might askwhy live spermatozoa do not all swimdownwards. The simplest explanationof the fact that they do not must, Isuppose, be that in a live spermatozoonthe specific gravities of the head and ofthe tail, though different, are such thatthe whole spermatozoon remains on aneven keel. 53

Fig. 13 is a diagram, based on cinema- atograph films, of the behaviour of li'vespermatozoa just after the direction FIG. 13.-Traci

the direction ofof streaming has been reversed. They right-hand linebehave quite differently from dead ones

in that they swim upstream in both halves of thesystem. Moreover, they turn so to swim upstream atright-angles to the direction of the velocity gradient-that is, in the horiizontal plane. At the moment we donot understand how spermatozoa do this, though acasual conversation with J. R. Pierce, of the BellTelephone Laboratories in the United States, may haveprovided a clue which is the subject of experimentsat the present time. It may be that spermatozoa havenot got sense organs like salmon, that the necessaryinformation is stored in the curvature of the velocitygradient, and that the velocity gradient itself turns thespermatozoa round.

directioni of flow

velocity profile

i1 ~~~~~x1

bFIG. 12.-Interpretation of the behaviour of dead bull spermato-zoa in a parabolic velocity gradient. The four spermatozoaA-D are sinking head first. The dotted sperm outlines show theapproximate positions they take up under the influence of the

velocity gradient.

Is there any point in spermatozoa swimming up-stream ? It is not even certain that they go up thefemale reproductive tract as a result of their own move-ments. They may be pulled up by movements of thetract. But even if they do swim upstream, is there aflow of fluid downt the female tract ? Or is it downin some parts-in the middle of the lumen, for example-and up in others, near the walls ? The answer to these

ks of human spermatozoa, originally swimming upstream, whenwf flow is reversed. The arrow shows the direction of flow. Theis 200 % long. The number at the end of each track is its duration

in seconds.

-y'

SEPT. 29, 1962 SPERMATOZOA 8.15

i --.:.D.ot

on 8 July 2020 by guest. Protected by copyright.

http://ww

w.bm

j.com/

Br M

ed J: first published as 10.1136/bmj.2.5308.812 on 29 S

eptember 1962. D

ownloaded from

816 SEPT. 29, 1962 SPERMATOZOA BRITISHIWEDICAL JOURNAL

questions cannot be given without further experiments-for example, by exteriorizing the female reproductivetract of a monkey and inserting flowmeters into it.(I doubt if radio-opaque liquids could be used to obtainthe answers.)

ChemotaxisSome organisms move up gradients of specific

chemicals-that is to say, they move preferentially fromregions of low to regions of high concentrations of thecompound in question. This is chemotaxis, or positivechemotaxis to be precise. (An organism is negativelychemotactic when it moves from a region of high toa region of low concentration of a compound.) Chemo-taxis depends on the existence of a gradient; if theconcentration of an attracting substance is everywherethe same in a suspension of living organisms, the latterobviously cannot react preferentially to the substancein a particular direction.Though the chemotaxis of spermatozoa towards

secretions from eggs has often been claimed to occur inthe animal kingdom, it is the exception rather than therule. There is little evidence for it among mammalsand it does not occur in sea-urchins. It does occur inone Japanese fish, and may do in bed-bugs and leeches,both of which have a highly atypical way of copulating

FA f/I, AS I0.0 0.1 0 2 0-3 0 4 0 5 06 007 08 0-9 [0

mm.

FIG. 14a.-Tracks of bracken spermatozoa swimming at random.

I1 - 1-- - i--'00 01 02 03 04 05 06 07 08 0(9 1-0

FIG. 14b.-Tracks of the same bracken spermatozoa after apipette containing 1 % malate was inserted into the .sperm

sutspension.

which makes it difficult for their spermatozoa to getto the right place, the site of the unfertilized eggs. Thesituation is quite different in the plant kingdom. Inferns, mosses, horsetails, liverworts, and quillworts thechemotaxis of spermatozoa towards secretions of eggs,or cells near them, is an established fact. The mos.famous case of sperm chemotaxis occurs in ferns. Theeggs or archegonia of bracken, for example, secreteL-malic acid into the external, aqueous medium. Agradient of L-malic acid attracts bracken spermatozoa,as can be seen in Fig. 14 a and b. In this experimenta drop of water containing bracken spermatozoa wasplaced on a microscope slide. A glass pipette containing1% sodium L-malate in water + 1", agar to preventcapillary effects or hydrodynamic flow was inserted intothe bracken sperm suspension. Malate ionls immediatelybegan to diffuse out of the tip of the pipette so that amalate gradient was set up.How selective are bracken spermatozoa ? The

following acids are reported to attract them: D-malic,mesotartaric, maleic, citraconic, and tartronic acids.This list might be thought to show that bracken sperma-tozoa are not particularly selective. But, althoughmaleic acid is an attractant, its enantiomorph, fumaricacid, is not.The mechanism by which plant spermatozoa swim

up gradients of organic acids is unknown. The mostobvious difference between plant and animal sperma-tozoa is that the former are multiflagellate, whereasanimal spermatozoa, with a few exceptions, areuniflagellate. Are some of the flagella of plant sperma-tozoa sense organs and not concerned with propulsion ?More cine-filmrs down the microscope might shed somelight on this question.

ConclusionThis year's Ingleby Lectures have been a review of

some of our knowledge of spermatozoa. Why shouldanyone be interested in them ? A suspension of sperma-tozoa is one of the most attractive systems on which abiologist can work. Spermatozoa move in an obviousway, unlike most living cells, and therefore tell usvisually whether they are alive or not; they respire;they glycolyse or fructolyse; they have all the enzymicgadgetry which in many other cases can be examinedonly in tissue slices or with the aid of that instrumentso dear to the heart of the biochemist, the homogenizer;parts of them are like, or are, muscle fibres, so thatsperm tails may help us to understand how musclescontract; they are easy, if sometimes frustrating, gamefor the electron-microscopist; they can appeal just aswell to the morphologist, the taxonomist, the appliedmathematician, or the biochemist; they are concernedwith some of the most important problems which affector afflict the world, over-population and sterility;finally, as their front ends consist almost entirely ofthe ultra-fashionable genetic codes or D.N.A., theyshould have enough glamour to enable us to get thesupport and interest we need tQ continue working onthem.

REFERENCESAfzelius, B. A., and Murray, A. (1957). Exp. Cell Res., 12, 325.Ballowitz, E. (1890a). Z. wiss. Zool., 50. 317.

(1890b). Arch. ndikr. Anat., 36. 225.(1917). Arch. Zellforsch., 14, 407.

Belaieff, W. (1898). Ber. dtsc/h. bot. Ges., 16, 140.Bloch, F. (1.935). Trav. Sta. _ool. Winiereulx, 12. 183.Dan, J. C., and Wada, S. K. (1955). Biol. Bull., Wood's [Hole,

1099 40.Ferguson. F. F. (1940). Zool. Anz~., 129, 21.

on 8 July 2020 by guest. Protected by copyright.

http://ww

w.bm

j.com/

Br M

ed J: first published as 10.1136/bmj.2.5308.812 on 29 S

eptember 1962. D

ownloaded from

SEPT. 29, 1962 SPERMATOZOA MEDICBAoHuRNAL 817

Franzen, A. (1955a). Zool. Bidr. Uppsala, 30, 399.(1955b). Ibid., 30, 485.(1956). Ibid., 31, 355.(1958). Ibid., 33, 1.

Gibbons, I. R. (1961). J. biophys. biochem. Cytol., 11, 179.Koltzoff, N. K. (1908). Arch. Zellforsch., 11, 1.Nath, V., and Bhatia, C. L. (1953). Res. Bull. E. Panjab Univ.,

No. 27, 33.and Sharma, G. P. (1952). Ibid., No. 22, 99.

Noyes, R. W., Walton, A., and Adams, C. E. (1958). J. Endocr.,17, 374.

Panijel, J. (1951). Metabolisme des Nucleoproteins. Hermannet Cie, Paris.

Retzius, G. (1906). Biologische Untersuchungen, 13.(1909). Ibid., 14.

Rothschild, Lord (1961). A Classification of Living Animals.Longmans, Green, London.

Seshachar, B. R. (1943). Proc. nat. Inst. Sci. India, 9, 271.Sharma, G. P. (1944). Ibid., 10, 305.- (1950). Res. Bull. E. Panjab Univ., No. 5, 67.Tuzet, O., and Sanchez, S. (1952). Arch. Zool. exp. g-n., 89, 26.Vasisht, H. S. (1954). Res. Bull. Panjab Univ., No. 62, 169.

PREGNANCY AND THYROTOXICOSIS*BY

PHILIP HAWE, Ch.M., F.R.C.S.Thyroid Clinic, David Lewis Northern Hospital,

LiverpoolAND

HAROLD H. FRANCIS, F.R.C.S., F.R.C.O.G.Department of Obstetrics and Gynaecology,

University of Liverpool

The association of thyrotoxicosis and pregnancy hasreceived little attention in the general medical literature.It is uncommon but important because the interactionof the two conditions may lead to serious consequencesfor the mother and for the child.The clinical data presented in this paper result from

a study of 70 pregnant patients treated during the 15years ending December 31, 1961, in the surgical unitsof the David Lewis Northern Hospital and WaltonHospital under the care of one of us (P. H.) and in thematernity units of the Liverpool Maternity Hospital andMill Road Maternity Hospital with which H. H. F. isassociated.

Physiologica ConsiderationsOne of the early effects of pregnancy in euthyroid

patients is a rise in the level of the plasma thyroxine-binding protein. This removes part of the circulatingfree thyroxine, and the pituitary responds by increasedproduction of thyrotropic hormone (T.S.H.). Hyper-plasia of the thyroid gland follows with increased outputof thyroxine (Figs. 1 and 2). These changes are reflectedby an increase in the protein-bound iodine (P.B.I.)and butanol-extractable iodine of the maternal blood,and readings well within the thyrotoxic range are usual(Benson et al., 1959). Concurrently with the hyper-plasia, uptake of radioiodine by the thyroid gland isincreased (Halnan, 1958). Elevation of the basal meta-bolic rate (B.M.R.) also takes place from the middletrimester onwards, and readings of +20% are to beexpected towards term; this is due to increased meta-bolism consequent on the gravid state and is not attribut-able directly to thyroid overactivity (Freedberg et al.,1957),*Paper presented to the North of England Obstetrical and

Gynaecological Society on November 17, 1961.C

There is good evidence of the passage of thyroxinethrough the placenta.in the later stages of pregnancy,although only small quantities are transmitted in thefirst few months (Myant, 1958; Grumbach and Werner,1956) (Fig. 3). Experimental evidence suggests that theplacenta is impervious to T.S.H. (Peterson and Young,1952; Feldman, 1960), but there may be exceptions.For example, thyrotoxic and exophthalmic babies havebeen born to mothers suffering from thyrotoxicosisand exophthalmos (Keynes, 1952; Levitt, 1954; Lewisand Macgregor, 1957; Riley and Sclare, 1957; Javettet al., 1959). Iodides and antithyroid drugs also passreadily through the placental barrier (Freiesleben andKjerulf-Jensen, 1947). The human foetal thyroid beginsto accumulate radioiodine at the end of the first trimester(Chapman et al., 1948) and thereafter 1311 is taken upby the foetal thyroid with even greater avidity than bythe maternal gland (Halnan, 1958).

Deficiency of thyroid function may be restricted eitherto the maternal or to the foetal gland, or may arisesimultaneously in both. According to Peterson andYoung (1952) and Man et al. (1958), if a seriousdeficiency of maternal thyroxine exists the foetus isunlikely to be nor-mal, but the extentto which the foetalthyroid can provide FREEfor the needs of thefoetus in the absence TO TISSUES-----of maternal thy- BOUND -T.S.H.roxine remains un- TO PLASMAcertain (Brit. med.J., 1957). Examples THYROXINE-!of normal childrenborn of myxoede-matous mothers have IODIDEb e e n recorded(Osorio and Myant, EUTHYROID1960). The fact that NON PREGNANTclinical evidence of .-Iodide uptake and thyroxine

secretion are controlled by thyro-hypothyroidism in tropic hormone (T.S.H.). Free andthe athyreotic child bound thyroxine are in simplettquilibrium in plasma. T.S.H. secre-is commonly absent tion is related to free thyroxine level.for the first fewweeks of life sug-gests that deficiencyof foetal thyroxine OESTROGENcan be offset bythyroxine secretedby the mother. FREE

THYROXINE! T.\\When hypothyroid- BOUND T. S.H.ism follows the use THYROXINE,of antithyroid drugs,function is depressedin both the foetaland maternal gland;this is a serioussituation and maylead to the develop- DDIDEment of foetal goitre EUTHYROIDand cretinism (Fig. PREGNANCY4). FIG. 2.-Rising oestrogen production

Diagnosis of increases thyroxine-binding protein inplasma. Free thyroxine is reducedThyrotoxicosis which evokes increased T.S.H. secre-During Pregnancy tion. Thyroid hyperplasia with in-

creased iodide uptake and thyroxineCertain clinical output follow. Concentration of

features, such as bound thyroxine (protein-bounid' l~~~odine) IS elevated and level of freeincreased cardiac thyroxine is restored.

on 8 July 2020 by guest. Protected by copyright.

http://ww

w.bm

j.com/

Br M

ed J: first published as 10.1136/bmj.2.5308.812 on 29 S

eptember 1962. D

ownloaded from